Biphenyl compounds and their use as oestrogenic agents

ABSTRACT

A method of treating osteoporosis in warm-blooded animals comprising administering to warm-blooded animals in need thereof an effective amount to treat osteoporosis of a compound selected from the group consisting of a compound of the formula:wherein the substituents are defined as in the Specification.

PRIOR APPLICATIONS

This application is a division of U.S. patent application Ser. No.09/896,943 filed Jun. 29, 2001 now U.S. Pat. No. 6,563,008, which is adivision of U.S. patent application Ser. No. 09/117,628 filed Sep. 28,1998, now U.S. Pat. No. 6,288,126, which is a 371 of PCT/FR97/00183filed Jan. 30, 1997.

The present invention relates to the use as medicaments of biphenylcompounds, the pharmaceutical compositions containing them, new biphenylcompounds, their preparation process and the intermediates of thisprocess.

A subject of the invention is as medicaments the compounds of generalformula (I):

in which R₁ and R₂, identical or different, represent a hydrogen atom, ahalogen atom, a hydroxyl radical, a trifluoromethyl radical, a nitroradical, an amino radical, an alkyloxy, alkylthio, alkylamino ordialkylamino radical, in which the alkyl contains from 1 to 8 carbonatoms, an —NR_(A)R_(B) group, in which R_(A) and R_(B) form with thenitrogen atom to which they are linked a saturated or unsaturatedheterocycle with 5 to 6 members optionally containing another heteroatomchosen from N, O and S, a linear or branched alkyl, alkenyl or alkynylradical, each containing at most 8 carbon atoms and optionallysubstituted, an aryl radical containing from 6 to 14 carbon atoms andoptionally substituted, an aralkyl radical containing from 7 to 15carbon atoms and optionally substituted, or a CH(OH)—Y or C(O)—Y radicalin which Y represents a substituted or non-substituted alkyl, alkenyl oralkynyl radical containing from 1 to 8 carbon atoms, or a substituted ornon-substituted aryl group containing from 6 to 14 carbon atoms, or alsoR₁ can form together with R₃ a —CH═CH—CH═CH— group, R₃ and R₄, identicalor different, represent a hydrogen atom, a halogen atom or an alkylradical containing from 1 to 8 carbon atoms, or R₃ can form togetherwith R₁ a —CH═CH—CH═CH— group, R₆ and R₇ identical or different,represent a hydrogen atom or a halogen atom, R₈ represents a hydrogenatom or an optionally substituted benzyl radical and R₅ represents an[A]—CH₃, —[A]—C(OH)ZZ′ or —[A]—C(O)Z″ group in which —[A]— represents alinear or branched alkylene, alkenylene or alkynylene radical eachcontaining at most 8 carbon atoms or a single bond, and Z, Z′ and Z″represent a hydrogen atom, an alkyl, alkenyl or alkynyl radicalcontaining up to 8 carbon atoms or an aryl radical containing from 6 to14 carbon atoms and optionally substituted, as well as their additionsalts with pharmaceutically acceptable acids and bases, it beingunderstood that there are excluded the compounds in which R₅ representsthe [A]—C(O)—Z″ group in which [A] is a single bond, Z″ is an alkylradical containing from 1 to 8 carbon atoms and R₁, R₂, R₃, R₄, R₆, R₇and R₈ are hydrogen atoms.

By halogen atom is meant fluorine, iodine, bromine and chlorine.

By alkyloxy radical containing from 1 to 8 carbon atoms, is preferablymeant the radical chosen from methoxy, ethoxy, propoxy, butoxy andpentoxy.

By alkylthio radical containing from 1 to 8 carbon atoms, is preferablymeant the radical chosen from methylthio, ethylthio, propylthio,isopropylthio and butylthio.

By alkylamino radical containing from 1 to 8 carbon atoms is preferablymeant the radical chosen from methylamino, ethylamino, propylamino,butylamino, pentylamino.

By dialkylamino radical each containing from 1 to 8 carbon atoms ispreferably meant the radical chosen from dimethylamino, diethylamino andmethylethylamino.

By —NR_(A)R_(B) group is preferably meant the group chosen frompyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiamorpholinyl andpyrrolyl.

By linear or branched alkyl, alkenyl or alkynyl radical, each containingat most 8 carbon atoms is preferably meant the radical chosen frommethyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, n-pentyl,n-hexyl, 2-methyl pentyl, 2,3-dimethyl butyl, n-heptyl, 2-methylhexyl,2,2-dimethyl pentyl, 3,3-dimethyl pentyl, 3-ethylpentyl, n-octyl,2,2-dimethylhexyl, 3,3-dimethylhexyl, 3-methyl 3-ethylpentyl, vinyl,propenyl, isopropenyl, allyl, 2-methylallyl, butenyl, isobutenyl,ethynyl, propynyl, propargyl, butynyl and isobutynyl and mostparticularly the methyl, ethyl, vinyl, propenyl, ethynyl and propynylradical.

By aryl radical containing from 6 to 14 carbon atoms and aralkylcontaining from 7 to 15 carbon atoms and optionally substituted, ispreferably meant a phenyl or benzyl radical optionally substituted by ahalogen atom chosen from fluorine, chlorine, bromine and iodine, analkyl radical having from 1 to 8 carbon atoms such as methyl, ethyl,propyl, isopropyl, butyl, isobutyl, tert-butyl, an alkoxy radical havingfrom 1 to 8 carbon atoms such as methoxy, ethoxy, propyloxy,isopropyloxy, butyloxy, an alkylthio radical having from 1 to 8 carbonatoms such as methylthio, ethylthio, propylthio, isopropylthio,butylthio, an amino, alkylamino radical having from 1 to 8 carbon atomssuch as methylamino or ethylamino, dialkylamino having 2 to 16 carbonatoms such as dimethylamino, diethylamino, methylethylamino, each ofthese dialkylamino radicals being optionally in oxidized form, anaminoalkyl radical having from 1 to 8 carbon atoms such as aminomethylor aminoethyl, a dialkylaminoalkyl radical having from 3 to 16 carbonatoms such as dimethylamino methyl or ethyl, a dialkylaminoalkyloxyradical having from 3 to 16 carbon atoms such as in particular thedimethylamino ethyloxy radical, a hydroxyl group, a free, esterifiedcarboxy group such as alkoxy carbonyl for example methoxy carbonyl orethoxy carbonyl or salified by a sodium or potassium atom, a cyanoradical, a trifluoromethyl radical, a nitro radical, a formyl radical, acarbamoyl radical, an acyl group such as acetyl, propionyl, butyryl orbenzoyl, acyloxy having up to 12 carbon atoms such as acetoxy or a groupof formula: —O—CO—(CH₂)_(m)CO₂H in which m is an integer ranging from 1to 5, an alkenyl radical such as vinyl or propenyl, an alkynyl radicalsuch as ethynyl or propynyl, an aryl radical such as phenyl, furyl,thienyl or aralkyl such as benzyl.

The expression “optionally substituted aryl” indicates that one or moresubstituents, identical or different, can be present in the ortho, metaor para position.

When R₁ and R₂ are substituted alkyl, alkenyl or alkynyl radicals, theyare the substituents as defined above.

The invention naturally extends to the salts of the compounds of formula(I), such as for example the salts formed when the compounds of formula(I) contain an amino function, with hydrochloric, hydrobromic, nitric,sulphuric, phosphoric, acetic, formic, propionic, benzoic, maleic,fumaric, succinic, tartaric, citric, oxalic, glyoxylic, aspartic,alkanesulphonic acids such as methane or ethanesulphonic acids,arenesulphonic acids, such as benzene or paratoluene sulphonic acids andarylcarboxylic acids, or when the compounds of formula (I) contain anacid function, with the salts of the alkali or alkaline earth metals orammonium optionally substituted.

A particular subject of the invention as medicaments is the compounds offormula (I) as defined previously corresponding to general formula (I′):

in which

either R′₅ represents an —[A]—CHO radical as defined previously and R₁,R₂, R₃, R₄, R₆, R₇ and R₈ are as defined previously, it being understoodthat when [A] represents a single bond and R₃, R₄, R₆, R₇ and R₈ arehydrogen atoms, R₁ and R₂ cannot simultaneously represent a hydrogenatom,

or R′₅ represents an —[A]—C(OH)ZZ′ group as defined previously and R₁,R₂, R₃, R₄, R₆, R₇ and R₈ are as defined previously, it being understoodthat when [A] represents a single bond and R₃, R₄, R₆, R₇, and R₈ arehydrogen atoms, R₁ and R₂ cannot simultaneously represent a hydrogenatom,

or R′₅ represents an —[A]—CH₃ radical as defined previously and R₁, R₂,R₃, R₄, R₆, R₇ and R₈ are as defined previously, it being understoodthat when R₃, R₄, R₆, R₇ and R₈ are hydrogen atoms, R₁ and R₂ cannotsimultaneously each represent a hydrogen atom, and it being understoodthat R₁, R₂, R₃ or R₄ cannot represent an alkyl radical or a halogenatom,

or R′₅ represents an [A]—C(O)Z″ radical as defined previously, R₁, R₂,R₃, R₄, R₆, R₇ and R₈ are as defined previously, it being understoodthat when [A] represents a single bond, R₃, R₄, R₆, R₇ and R₈ arehydrogen atoms, and Z″ is an alkyl radical containing from 1 to 8 carbonatoms, so R₁ and R₂ cannot simultaneously each represent a hydrogenatom, or cannot represent a nitro or hydroxyl radical, as well as theiraddition salts with pharmaceutically acceptable acids and bases.

A more particular subject of the invention as medicaments is thecompounds of general formula (I′) as defined previously, in which R₁,R₂, R₃, R₄, R₆, R₇ and R₈ are as defined previously and in which —[A]—represents a single bond, as well as the addition salts withpharmaceutically acceptable acids or bases.

When R′₅ represents an [A]—C(O)Z″ group, [A] is preferably a singlebond. This is preferably a radical chosen from formyl, acetyl,propionyl, butyryl and benzoyl.

A quite particular subject of the invention as medicaments is thecompounds of formula (I′) as defined previously in which R₁, R₂, R₃, R₄,R₆R₇ and R₈ have the same meaning as previously and in which R′₅represents a formyl radical as well as the addition salts withpharmaceutically acceptable acids or bases.

A quite particular subject of the invention is also as medicaments thecompounds of formula (I′) as defined previously in which R₁, R₂, R₃, R₄,R₆, R₇ and R₈ have the same meaning as previously and in which R′₅represents an —[A]—C(OH)ZZ′ group as defined previously, as well as theaddition salts with pharmaceutically acceptable acids or bases.

When, R′₅ represents an [A]—C(OH)ZZ′ radical, [A] is preferably a singlebond or an alkylene group of formula —(CH₂)_(n)—, in which n representsan integer comprised between 1 and 8, such as —CH₂—, —CH₂CH₂—,—CH₂CH₂CH₂— or —CH₂CH₂CH₂CH₂—, Z and Z′ preferably represent a hydrogenatom, an alkyl radical or a phenyl radical.

A most particular subject of the invention as medicaments is thecompounds of formula (I′) as defined previously in which R′₅ representsa CH₂OH radical and R₁, R₂, R₃, R₄, R₆, R₇ and R₈ have the same meaningas previously as well as the addition salts with pharmaceuticallyacceptable acids and bases.

When R′₅ represents an [A]—CH₃ radical, [A] is preferably a single bondor a CH₂, CH(CH₃), C(CH₃)₂, CH₂CH₂, CH₂CH₂CH₂ or CH₂CH₂CH₂CH₂ group.

A more particular subject of the invention is as medicaments thecompounds of formula (I′) as defined previously in which R₆, R₇ and R₈are hydrogen atoms.

A more particular subject of the invention is as medicaments thecompounds of formula (I′) as defined previously in which R₆ and R₇ arehydrogen atoms and R₈ is a benzyl group.

A quite particular subject of the invention as medicaments is thecompounds of formula (I′) as defined previously in which R₁ and R₂identical or different are halogen atoms and R₃, R₄, R₆, R₇ and R₈ arehydrogen atoms.

A quite particular subject of the invention as medicaments is thecompounds of formula (I) as defined previously corresponding to generalformula (I″):

in which R′₁ represents an aryl group containing from 6 to 14 carbonatoms and optionally substituted, R′₂ represents a halogen atom, a nitroradical or an amino radical, as well as the addition salts withpharmaceutically acceptable acids and bases.

A quite particular subject of the invention as medicaments is thecompounds of formula (I) as defined previously corresponding to generalformula (I″) as defined above in which R′₁ represents a phenyl radicalsubstituted by a dialkylaminoalkyloxy group having 3 to 16 carbon atomsand more particularly the dimethylaminoethyloxy radical, as well as theaddition salts with pharmaceutically acceptable acids and bases.

A more specific subject of the invention as medicaments is the compoundsof formula (I) as defined previously the names of which follow:

2,6-dibromo-4′-hydroxy-(1,1′-biphenyl)-4-methanol,

2,6-dichloro-4′-hydroxy-(1,1′-biphenyl)-4-methanol,

2,6-dinitro-4′-hydroxy-(1,1′-biphenyl)-4-methanol,

4,4″-dihydroxy-(1,1′:2′,1″-terphenyl)-5′-methanol,

1-[2-chloro-4′-hydroxy-3-methyl-6-(1-methylethyl))-(1,1′-biphenyl-4-yl)]-ethanone,

2-bromo-4′-hydroxy-6-nitro-(1,1′-biphenyl)-4-methanol,

1-[2-chloro-4′-hydroxy3-methyl-6-(1-methylethyl)-(1,1′-biphenyl-4-yl)]-ethanol,

4′-hydroxy-2-trifluoromethyl-(1,1′-biphenyl)-4-methanol,

4′-methyl-2′-trifluoromethyl-(1,1′-biphenyl)-ol,

2,6-dichloro-4′-hydroxy-(1,1′-biphenyl)-4-carboxaldehyde,

2-chloro-4′-hydroxy-6-(1-methylethyl)-(1,1′-biphenyl)-4-methanol,

2-chloro-4′-hydroxy-6-trifluoromethyl-(1,1′-biphenyl)-4-methanol,

2,6-dichloro-4′-hydroxy-5′-(phenylmethyl)-(1,1′-biphenyl)-4-methanol,

2-bromo 6-[[4-[2-(dimethylamino) ethoxy] phenyl] hydroxymethyl]4′-hydroxy (1,1′-biphenyl) 4-methanol,

[6-bromo 4′-hydroxy 4-(hydroxymethyl) (1,1′-biphenyl) 2-yl][4-[2-(dimethylamino) ethoxy] phenyl] methanone,

6′-bromo 4-[2-(dimethylamino) ethoxy] 4″-hydroxy (1,1′:2′,1″-terphenyl)4′-methanol,

4-[2-(dimethylamino) ethoxy] 4″-hydroxy 6′-nitro (1,1′:2′,1″-terphenyl)4′-methanol,

6′-chloro 4,4″-dihydroxy (1,1′:2′,1″-terphenyl) 4′-methanol.

The Applicant has demonstrated that the compounds of formula (I) as wellas their addition salts with pharmaceutically acceptable acids and basesare particularly useful products from a pharmacological point of view.They are original ligands of the oestrogen receptor.

As such, the products of formula (I) can be used in the treatment ofdisorders linked to hypofolliculinemia, for example, amenorrheas,dysmenorrheas, repeated abortions, premenstrual disorders, in thetreatment of certain oestrogen-dependent pathologies such as prostaticadenomas or carcinomas, mammary carcinomas and their metastases or inthe treatment of benign tumours of the breast, both as anantiuterotropic as well as in the replacement treatment of symptomslinked to the menopause and in particular of osteoporosis.

The invention extends to the pharmaceutical compositions containing atleast one medicament as defined above as active ingredient.

The compounds of formula (I) are used by digestive, parenteral or localroute, for example by percutaneous route. They can be prescribed in theform of simple or sugar-coated tablets, capsules, granules,suppositories, pessaries, injectable preparations, ointments, creams,gels, microspheres, implants, patches, which are prepared according tothe usual methods.

The active ingredient or ingredients can be incorporated with excipientsusually used in these pharmaceutical compositions, such as talc, gumarabic, lactose, starch, magnesium stearate, cocoa butter, aqueous ornon-aqueous vehicles, fatty substances of animal or vegetable origin,paraffin derivatives, glycols, various wetting, dispersion oremulsifying agents, preservatives.

The dose varies according to the illness to be treated and theadministration route: it can vary for example from 1 mg to 100 mg by dayin adults by oral route.

Certain products of formula (I) are new and are therefore a subject ofthe present invention.

Others are known.

Certain products of general formula (I) with R₅ representing an[A]—C(OH)ZZ′ group and R₁, R₂, R₃, R₄, R₆, R₇ and R₈ are hydrogens, areknown as intermediate synthetic products or also in the field of liquidcrystals. There can be mentioned the following examples:

R₅ = CH(CH₃)OH US 5218124 (1993) R₅ = CMe₂OH DE 3402831 (1984)

Certain products of general formula (I) with R₅ representing an [A]—CH₃group are used in the field of liquid crystals. There can be mentionedthe following examples:

R₁═Cl and R₅=n-Pentyl, Liq. Cryst. 10(6), 799-802

R₁═Me and R₅=n-Pentyl, Liq. Cryst. 10(6), 799-802

R₁═F, R₂=F and R₅=n-Pentyl, GB2257701 (Feb. 1, 1993)

R₃═Cl and R₅=n-pentyl, CA116-107805.

Certain products of general formula (I) with R₅ representing an [A]—COZ″group containing from 2 to 8 carbon atoms are for their part used assynthetic intermediate products (CA 120 77179u R₅=acetyl and R₁═NO₂) oralso in the field of liquid crystals (CA 111 245029e R₅═C(O)C₅ andR₁═OH).

Certain products of general formula (I) with R₅ representing an [A]—CHOgroup and R₁, R₂, R₃, R₄, R₅, R₆, R₇ and R₈ are hydrogens are known assynthetic intermediate products or also in the field of liquid crystals.There can be mentioned the following example:

R₅═CHO JP01207254 (1989).

Certain products of general formula (I) with R₅ representing an [A]—COOHgroup are known. There can be mentioned the following example:

R₅═—(CH₂)_(n)—COOH, n=0, 1 or 2 and R₁═R₂═I or Cl: A. Dibbo et al. J.Chem. Soc. (1961) 2890-2902.

Thus a subject of the invention is also the use, as a medicament, on theone hand of known products of general formula (I) and on the other handof new products of general formula (I).

Therefore a subject of the invention is also new compounds of generalformula (I) corresponding to formula (I′) as described previously, aswell as their addition salts with acids and bases.

A quite particular subject of the invention is the compounds of generalformula (I) as defined previously listed above.

Another particular subject of the invention is new compounds of formula(I) as defined previously corresponding to general formula (I″) asdefined above as well as their addition salts with acids and bases.

A subject of the invention is also a preparation process for products offormula (I′) as defined above characterized in that a product of formula(II):

in which R₁, R₂, R₃ and R₄ are as defined previously and R_(5A) has thevalues of R′₅ as defined previously as well as the hydrogen oresterified or non esterified —[A]—CO₂H values and X represents ahydrogen atom, halogen or an OSO₂CF₃ group, is subjected to the action,in the presence of a catalyst, of a product of formula (III):

in which R₆ and R₇ are as defined previously, Y represents a hydrogenatom, halogen, a B(OH)₂ group or an Sn(R)₃ group, in which R representsan alkyl group containing from 1 to 8 carbon atoms, and P represents aprotective group, in order to obtain a product of formula (IV):

in which P, R₁, R₂, R₃, R₄, R_(5A), R₆ and R₇ have the same meaning aspreviously, which product of formula (IV) if desired or if necessary issubjected in an appropriate order to one or, if appropriate, several ofthe following reactions in order to obtain the product of formula (I′):

deprotection of the phenol,

debenzylation then rearrangement in order to obtain a product of formula(I) with R₈=benzyl,

total or partial reduction of the NO₂ groups which can be represented byR₁ or R₂ into NH₂,

substitution of NH₂ which can be represented by R₁, R₂, R₃ or R₄, by Bror by I,

formylation reaction when R_(5A) represents a hydrogen atom,

reduction of the esterified —[A]—CO₂H function which can be representedby R_(5A),

saponification,

reduction of the —[A]—CHO group which can be represented by R_(5A) intoan —[A]—CH₂OH group,

oxidation of the —[A]—CHO group which can be represented by R_(5A) intoan —[A]—CO₂H group,

esterification of the —[A]—CO₂H group which can be represented byR_(5A),

reduction of the acyl function which can be represented by R_(5A) intothe corresponding alcohol, or into the corresponding alkyl radical,

Wittig's reaction on the [A]—CHO function which can be represented byR₅A in order to obtain an [A]—CH═CH—CHO group, then reduction of theunsaturated aldehyde in order to obtain the corresponding alcohol offormula [A]—CH═CH—CH₂OH,

Wittig's reaction on the [A]—CHO function which can be represented byR_(5A) in order to obtain an [A]—CH₂—CHO group, then reduction of the[A]—CH₂—CHO aldehyde in order to obtain the corresponding alcohol offormula [A]—CH₂—CH₂OH,

reduction reaction when [A] represents a bivalent alkenylene oralkynylene radical,

action of an organometallic on the aldehyde, the ketone or theesterified acid which can be represented by R_(5A),

formation of a pyrrole group from NH₂,

substitution of NH₂ by an S-Alkyl group, and salification by an acid ora base.

Formation of the biphenyls of formula (IV) by coupling of the aromaticcompound of formula (II) with the aromatic compound of formula (III) iscarried out either in the presence of a catalyst chosen from palladiumderivatives in the case where:

(a) Y represents a B(OH)₂ or Sn(R)₃ group and X represents an OSO₂CF₃group, a bromine atom or an iodine atom,

and thus can be carried out under the conditions described in thefollowing articles when Y represents a B(OH)₂ group:

A. Huth, I. Beetz and I. Schumann Tetrahedron (1989) 45 6679:Conditions: Na₂CO₃ 2M/Pd(PΦ₃)₄/Toluene/LiCl/EtOH/Δ

J. K. Stille et al. Ang. Chem. Int. Ed. (1986) 25 508: Conditions:Pd(PΦ₃ )₄/LiCl/Dioxane/Δ

T. Oh-e, N. Migawa and A. Suzuki J. Org. Chem. (1993) 58 2201-2208:Conditions: K₃PO₄/KBr/Pd(PΦ₃ )₄/Dioxane/Δ

Suzuki et al., Synlett (1992) 208

Conditions: Pd(PΦ₃)₄/Ba(OH)₂/DMEaq;

or also when Y represents an SnBu₃ group, under the conditions describedin the following articles:

J. K. Stille et al, J. Am. Chem. Soc. (1987) 5478-5480 or by V. Farina,J. Org. Chem. (1993) 58 5434;

or in the presence of copper in the case where:

(b) Y represents an iodine atom and X represents a chlorine atom,

(c) Y represents a chlorine atom and X represents an iodine atom,

and thus can be carried out under the conditions described in thefollowing:

P. E. Fanta Chem. Rev. (1964) 38 139 or synthesis (1974) 9: Conditions:Cu/DMF/120° C.;

or in the presence of a strong base and of ZnCl₂ then a catalyst chosenfrom palladium derivatives in the case where:

(d) Y represents a bromine atom and X represents a hydrogen atom,

(e) Y represents a hydrogen atom and X represents a bromine atom,

and thus can be carried out under the following conditions:

1) nBuli/THF/−768° C.

2) ZnCl₂

3) ArBr/Pd(PΦ₃)₄/Δ

4) HCl/MeOH.

The orthometalation reactions are described for example in the followingdocuments:

T. KRESS Synthesis (1983) 803,

N. IWAO J. Org. Chem. (1990) 55 3623.

Moreover, the exchange reaction with ZnCl₂ followed by a couplingreaction has been described by E. Negishi in J. Org. Chem. (1977) 42182.

The protective group P preferably represents an alkyl radical containingfrom 1 to 4 carbon atoms, a benzyl group, an R_(C)R_(D)R_(E)Si group, inwhich R_(C), R_(D) and R_(E) identical or different, independently ofone another each represent an alkyl radical containing from 1 to 4carbon atoms or a phenyl group. This is most particularly theSi(Me)₂C(Me)₃ or —Si(Ph)₂C(Me)₃ groups.

Deprotection reactions are the standard deprotection methods known to aperson skilled in the art. A fairly complete review is provided in thefollowing work: Protective groups in organic synthesis, T. W Greene,John Wiley & sons (1981).

As an example the deprotection reactions when P is a methyl radical canbe carried out by the action of tribromoborane in dichloromethane orhydrochloric acid in pyridine, the deprotection reactions when P is abenzyl group can be carried out by the action of hydrogen in thepresence of palladium on carbon in ethyl acetate, by the action oftrifluoroacetic acid or by the action of trimethylsilyl iodide. Thedeprotection reactions when P is a tertbutyldiphenylsilyl group can becarried out by the action of tetrabutyl ammonium fluoride (TBAF) insolution in tetrahydrofuran.

At the time of the debenzylation reaction by the action oftrifluoroacetic acid, a rearrangement and formation of a deprotectedderivative with R₈=benzyl can be obtained.

The reduction reaction of the NO₂ radical which can be represented by R₁or R₂ into an NH₂ radical can be carried out by the action of tindichloride in ethanol under reflux and the monoreduction reaction ispreferably carried out by the action of cyclohexene in the presence ofpalladium dihydroxide in ethanol or tetrahydrofuran under reflux.

The substitution reaction of NH₂ which can be represented by R₁ or R₂ byBr is preferably carried out by the action of hydrobromic acid in thepresence of sodium nitrite and of copper bromide in water at 0° C. or bythe action of tribromomethane in the presence of terbutylnitrite.

The substitution reaction of NH₂ by iodine is preferably carried out bythe action of potassium iodide in the presence of sodium nitrite andsulphuric acid or by the action of iodine in the presence ofterbutylnitrite.

The formylation reaction when R_(5A) is a hydrogen atom can be carriedout in the presence of dimethylformamide and a strong base such asn-butyllithium then hydrolysis with a mineral acid such as hydrochloricacid.

The reduction reaction of the esterified —[A]—CO₂H function which can berepresented by R_(5A) in order to obtain the corresponding alcohol iscarried out for example by the action of lithium aluminium hydride intetrahydrofuran.

There is particularly meant by esterified —[A]—CO₂H, the —CO₂Me and—CO₂Et groups.

The saponification reaction of the ester function which can berepresented by R_(5A) into the corresponding acid is carried out forexample by the action of an alkaline base such as soda or potash intetrahydrofuran or a lower alcohol such as methanol or ethanol.

The reduction reaction of the [A]—CHO group which can be represented byRSA into an [A]—CH₂OH group is carried out for example by the action ofsodium borohydride in methanol at 0° C. or by the action of hydrogen inthe presence of palladium on carbon in ethyl acetate.

The oxidation reaction of the [A]—CHO group which can be represented byR_(5A) into an [A]—CO₂H group can be carried out by the action of Jonesreagent (chromic acid/sulphuric acid) in a neutral solvant such asacetone, by the action of silver oxide in tetrahydrofuran and 2N soda orby the action of sodium hypochlorite in the presence of aminosulphonicacid.

The esterification reaction of the —[A]—CO₂H group which can berepresented by R_(5A), can be carried out by the action of ethanol ormethanol in the presence of a strong acid such as hydrochloric orsulphuric acid.

The reduction reaction of the [A]—C(O)—Z″ group which can be representedby R_(5A) into the corresponding alcohol can be carried out for exampleby the action of sodium borohydride in methanol.

The reduction reaction of the [A]—C(O)—Z″ group which can be representedby R_(5A) into the corresponding alkyl can be carried out by the actionof hydrogen in the presence of palladium on carbon in ethyl acetate.

Wittig's reaction on the [A]—CHO function which can be represented byR_(5A) in order to obtain an [A]—CH═CH—CHO group, is carried out by theaction of phosphine Φ₃P═CH—CHO.

The reduction of the unsaturated aldehyde [A]—CH═CH—CHO in order toobtain the corresponding alcohol of formula [A]—CH═CH—CH₂OH can becarried out by the action of the sodium borohydride in the presence ofCeCl₃, 7H₂O in methanol.

Wittig's reaction on the [A]—CHO function which can be represented byR_(5A) in order to obtain an [A]—CH₂—CHO group (homologation reaction)is carried out by the action of phosphine Φ₃P—CH₂OMe or Φ₂P(O)—CH₂OMe.

The reduction of the aldehyde [A]—CH₂—CHO in order to obtain thecorresponding alcohol of formula [A]—CH₂—CH₂OH can be carried out by themethods described above.

The total or partial reduction reaction when [A] represents a bivalentalkenylene or alkynylene radical can be carried out either totally bythe action of hydrogen in the presence of a catalyst such as palladiumon carbon or a rhodium catalyst such as Wilkinson's reagent or partially(alkynylene becomes alkenylene) by the action of a poisoned catalystsuch as palladium on barium sulphate.

The action of an organometallic on the aldehyde, the ketone or theesterified acid which can be represented by R_(5A) provides access tothe products of formula (I′) in which R′₅ represents —[A]—C(OH)ZZ′, Zand Z′ represents an optionally substituted alkyl, alkenyl, alkynyl oraryl radical.

The organometallic derivative of a phenyl, alkyl, alkenyl or alkynylradical is chosen from the magnesium compounds of formula AlkMgHal orArMgHal and the lithium compounds of formula AlkLi or PhLi in which Alkrepresents an alkyl, alkenyl or alkynyl group containing at most 8carbon atoms. Ar represents an optionally substituted phenyl and Halrepresents a halogen atom. In a preferred implementation of the process,Hal represents a chlorine, bromine or iodine atom, preferably bromine.The reaction medium can then be subjected to a strong acid such ashydrochloric acid or sulphuric acid.

For example the action of Z—MgBr on the compounds of formula (I′) inwhich R′₅═CHO provides access to the compounds of formula (I′) in whichR′₅═—CH(Z)—OH.

For example the action of PhMgBr on the compounds of formula (I′) inwhich R′₅═CHO provides access to the compounds of formula (I′) in whichR′₅═—CH(Ph)—OH.

For example, the action of Z—MgBr on the compounds of formula (I′) inwhich R′₅═COCH₂CH₃ provides access to the compounds of formula (I′) inwhich R′₅═—C(OH)(Z)(Et).

For example, the action of PhMgBr on the compounds of formula (I′) inwhich R′₅═COCH₂CH₃ provides access to the compounds of formula (I′) inwhich R′₅═—C(Ph)(Et)—OH.

For example, the action of MeMgBr on the compounds of formula (IV) inwhich R_(5A)═CO₂Me provides access to the compounds of formula (IV) inwhich R_(5A)═—C(Me)₂—OH.

The formation of an unsaturated heterocycle such as pyrrole from thecorresponding amine is carried out by the action of 2,5dimethoxytetrahydrofuran in the presence of acetic acid.

The substitution reaction of an amine by S-Alkyl is carried out by theaction of (Alkyl-S)₂ in the presence of tBuNO₂.

Salification can be carried out under the usual conditions. Theoperation is carried out for example in the presence of ethanolic soda.A sodium salt can also be used such as the carbonate or the carbonateacid of sodium or of potassium.

Similarly, salification by an acid is carried out under the usualconditions. The operation is carried out for example with hydrochloricacid, for example in an ethereal solution.

A particular subject of the invention is a preparation process forproducts of formula (I″) as defined above characterized in that acompound of formula (VII):

in which Alk′ and P′ identical or different, each represent an alkylradical containing from 1 to 4 carbon atoms and R′₁ and R′₂ are asdefined previously, is subjected to the action of a deprotection orreducing reagent of the ester function in order to obtain the product offormula (I″) then, if desired, is subjected to the action of a base oran acid in order to obtain the corresponding salts.

This product of formula (VII) corresponds to products of formula (IV) inwhich P represents an alkyl radical containing from 1 to 4 carbon atoms,R₂, R₃, R₄, R₆, R₇ and R₈ are hydrogen atoms, R₁ represents anoptionally substituted aryl radical and R_(5A) represents an esterified—CO₂H group.

A process for the formation of products of formula (VII), with R′₁representing a Ph—OH group, P and Alk representing a methyl, isdescribed in the following reference:

J. Med. Chem. (1989) 32 1814-1820.

By analogy, this process can thus be extended to all the products offormula (V) with R′₁ representing an optionally substituted aryl groupcontaining from 6 to 14 carbon atoms.

Thus a compound of formula (V):

in which R′₁ represents an optionally substituted aryl group and P′represents an alkyl radical containing from 1 to 4 carbon atoms, issubjected to the action of a compound of formula (VI):

in which Alk′ represents an alkyl radical containing from 1 to 4 carbonatoms and R′₂ is as defined previously, in order to obtain a compound offormula (VII).

The action of the alkylcoumarate of formula (VI) on the compound offormula (V) in order to obtain the compound of formula (VII) ispreferably carried out under nitrogen pressure at a temperature of 250°C. in toluene. This reaction is described in the following reference: J.Med. Chem. (1989) 32 1814-1820.

The products of formula (V) are known or are easily accessible to aperson skilled in the art by applying the general principles offunctionalization of aromatic compounds. There can be mentioned asexamples a few references:

W09309079 (R′₁═Ph and P′═Me), J. Organomet. Chem. 395(2), 277-9(R′₁═Ph—OCH₂CH₂NMe₂ and P′═Me,).

The products of formula (VI) with R′₂═H, are also known. There can bementioned the following reference: J. Med. Chem. (1989) 32 1814-1820.

The products of formula (VI) with R′₂ different from H, are known oreasily accessible to a person skilled in the art. For example, theproducts of formula (VI) with R′₂═Cl are formed by action ofN-chlorosuccinimide on the product of formula (VI) with R′₂═H.

The products of general formula (II) are en general connus or areaccessibles to a person skilled in the art by applying the generalprinciples of functionalization of aromatic compounds.

The products of formula (II) with X═0Tf (triflates) are obtained fromthe corresponding alcohols of general formula (II′):

by the action of triflic anhydride action in pyridine at 0° C. accordingto the method described by Scott W. J., Stille J. K., J. Am. Chem. Soc.(1986) 108 3033.

The products of general formula (II′) are for their part generally knownto or are accessible by a person skilled in the art by applying thegeneral principles of the chemistry of aromatic compounds. There can bementioned among others the following reference: RODD'S CHEMISTRY OFCARBON COMPOUNDS Vol III Aromatic compounds Ed. M. F. ANSELL ElsevierScientific Publishing Company (1981).

The products of formula (II) with X=I (iodated products) can be obtainedby orthometallation from the corresponding non-iodated aromatic productsof general formula (II″):

in particular by the action of N-iodosuccinimide or iodine in thepresence of a strong base such as n-Butyllithium in tetrahydrofuran at−78° C.

The products of general formula (II″) are for their part generally knownto or are accessible by a person skilled in the art by applying thegeneral principles of the chemistry of aromatic compounds.

In the case where R_(5A) is an —[A]—CO₂H, [A]—C(O)Z″ or —[A]—C(OH)ZZ′group it will be necessary to provide the adequate protections known toa person skilled in the art in particular during the preparation of theproducts of general formula (II) from products of general formulae (II′)and (II″). As an example, the —[A]—CO₂H group can be esterified, theformyl or acyl group can be protected in the form of an acetal such asdioxolane by the action of glycol in the presence of paratoluenesulphonic acid, the hydroxyl group can be protected in the form of atetrahydropyrranyloxy group (OTHP) by the action of dihydropyrrane.

The products of formula (III) are known or accessible from protectedparabromophenol or from parabromoanisole by the following methods: Theproducts of formula (III) with Y representing the B(OH)₂ group and Prepresenting a methyl radical can first be obtained by the action ofparabromoanisole with Mg turnings in anhydrous diethyl ether underreflux, then by the action of triethylborate in anhydrous diethyl etherat −70° C., then hydrolysis with a strong mineral acid such as sulphuricacid.

The products of formula (III) with Y representing the B(OH)₂ group canalso be obtained by the action of parabromophenol protected by aprotective group P such as benzyl or terbutyldiphenyl silyl, withtriethylborate in the presence of n-butyllithium in tetrahydrofuran at−78° C. followed by hydrolysis with a strong mineral acid such assulphuric acid or with water.

The products of formula (III) with Y representing the SnBu₃ group can beobtained by the action of parabromophenol protected by a protectivegroup P such as tertbutyldiphenylsilyl, with tin tributyl chloride inthe presence of n-butyllithium in tetrahydrofuran at −78° C.

The products of formula (III) with Y representing an iodine atom and Prepresenting a benzyl or terbutyldiphenylsilyl group can be obtained bythe action of paraiodophenol with a protective group as defined above.

A subject of the invention is also as new industrial products and inparticular new intermediates necessary for the implementation of theinvention, the products of general formula (IV) with the exception ofthe product of formula (IV) in which R_(5A) represents an esterified ornon esterified [A]—CO₂H radical.

The following examples illustrate the invention without however limitingit.

Preparation 1 (4-methoxyphenyl)-boronic acid

100 ml of a solution of 10 g of p-bromoanisole in anhydrous diethylether is added dropwise under reflux to a suspension, under inert gas,of 1.3 g of magnesium turnings in 5 ml of anhydrous diethyl ether, andthe mixture is left under reflux for 2 hours. The reaction medium isthen poured into a solution of 9.02 ml of triethylborate in 60 ml ofanhydrous ether cooled down to −70° C. After agitation for 1 hour at−70° C., then for 1 hour at ambient temperature, the solution is pouredinto a mixture comprising 11 ml of sulphuric acid and 50 g of ice andwater followed by agitation for 1 hour. The organic phase is extractedwith 100 ml of an aqueous solution saturated in sodium bicarbonate, theaqueous phases are combined, then reacidified with 6N hydrochloric acid,extracted with ether, dried and evaporated under reduced pressure. 3.9 gof expected product is obtained.

I.R. spectrum: (Nujol)

Complex absorption OH/NH region, 1609, 1573 and 1518 cm⁻¹ NMR (DMSO-d6,300 MHz)

3.76 s OCH ₃ 6.88 d J = 9 Hz H₃ and H₅ 7.78 d J = 9 Hz H₂ and H₆ 7.86B(OH)₂

Preparation 2 [4-(phenylmethoxy)phenyl]-boronic acid

Stage A: 1-bromo-4-(phenylmethoxy)-benzene

15.26 g of 50% sodium hydride in oil is added, at 0° C., to a solutionunder inert gas of 50 g of parabromophenol in 320 ml ofdimethylformamide, followed by agitation for 30 minutes at 0° C., then37.7 ml of benzyl bromide is added. Agitation is carried out for 2 hours30 minutes while allowing the temperature to return to 20° C., then thereaction mixture is poured into ice-cooled water, the precipitate isfiltered and dried. 73.35 g of expected product is obtained.

Rf: 0.85 (thin layer chromatography, support: silica, eluant:

cyclohexane/ethyl acetate 7/3).

I.R. spectrum: (CHCl₃)

Absence of OH

Aromatic 1592, 1580 and 1488 cm⁻¹

Stage B: [4-(phenylmethoxy)phenyl]-boronic acid

143 ml of a solution of n-Butyllithium is added, dropwise, under inertgas and at −78° C., to 47.08 g of the product obtained in Stage A in 375ml of tetrahydrofuran, agitation is carried out for 1 hour, then 36.5 mlof triethylborate is added. Agitation is carried out for 14 hours, whileallowing the temperature to return to 20° C., and the reaction medium ishydrolyzed using a solution of ice-cooled water containing 45 ml ofconcentrated sulphuric acid, for 1 hour at 20° C. The aqueous phase isextracted with ethyl acetate, the organic phases are washed with 2N sodaand the aqueous phase is acidified to pH=1 using a solution of INhydrochloric acid in order to precipitate the boronic acid. Afterfiltration and drying the precipitate 28.54 g of expected product isobtained.

Rf: 0.16 cyclohexane/ethyl acetate 7/3)

I.R. spectrum: (Nujol)

General absorption 3650, 3615, 3510 and 3420 cm⁻¹ OH/NH region Aromatic1605, 1570 and 1510 cm⁻¹ B—O 1410, 1340 cm⁻¹

Preparation 3 [4-[[(1,1-dimethylethyl)diphenylsilyl]oxy]phenyl]-boronicacid

Stage A: 1-Bromo-4-[[(1,1-dimethylethyl)diphenylsilyl]oxy]benzene

400 ml of dimethylformamide, 31.18 g of imidazole and 125.89 g of1,1-dimethyl-ethyldiphenyl-chlorosilane are added under an inertatmosphere and at ambient temperature to 80.89 g of parabromophenol,then the solution obtained is agitated for 2 hours. The reaction mediumis poured into 2 litres of water, precipitation is observed, the solidis solubilized with ethyl acetate and the aqueous phase is extractedwith ethyl acetate, the combined organic phases are dried and evaporatedunder reduced pressure until an oil is obtained. Pentane is added andcrystallisation is observed. After filtration and drying of theprecipitate 179.24 g of expected product is obtained. Rf: 0.53 (thinlayer chromatography, support: silica, eluant Cyclohexane/AcOEt 95/5).

Melting point: 56° C.

NMR (CDCl₃, 300 MHz)

1.09 s Si—tBu 6.63 m H₃, H₅ 7.17 m H₂, H₆ 7.69 dd 4 H for SiΦ2 7.4 6 Hfor SiΦ2

Stage B: [4-[[(1,1-dimethylethyl)diphenylsilyl]oxy] phenyl]-boronic acid

60 ml of a solution of n-butyl-lithium is added, dropwise, at −78° C.and under inert gas, to a solution of 30 g of the product of theprevious stage in 100 ml of anhydrous tetrahydrofuran, followed, afteragitation for 30 minutes at −78° C., by the addition of 9.95 ml oftrimethylborate. After agitation for 2 hours 30 minutes, while allowingthe reaction medium to return to ambient temperature, 20 ml of water isadded dropwise and agitation is carried out for 72 hours. Afterevaporation of the tetrahydrofuran under reduced pressure, the aqueousphase is extracted with ether, dried and concentrated under reducedpressure until an oil is obtained (26.35 g) which is purified byfiltration chromatography on silica with a hexane/ethyl acetate mixture1/1 in order to obtain 7.73 g of expected product in the form of thetrimer and the monomer.

IR (CHCl₃) O—Si 915 and 1255 cm⁻¹ B—O 1350 and 1370 cm⁻¹ Aromatics 1515,1570 and 1602 cm⁻¹ NMR (CDCl₃) 1.11 tBu 6.81 and 7.88 Ph—O 7.3 to 7.5 (6H) and 7.72 (4 H) PhSi

Preparation 4 [4-[[(1.1-dimethylethyl)diphenylsilyl]oxy]phenyl]-tributyl tin

123.89 ml of a solution of sec-butyl-lithium (1.13 M) is added,dropwise, at −50° C. and under inert gas, to a solution of 50 g of theproduct of Stage A of Preparation 3 in 300 ml of anhydroustetrahydrofuran, then after agitation for 1 hour at −50° C., 36.29 ml oftributyl tin chloride is added. After agitation for 30 minutes, whileallowing the reaction medium to return to ambient temperature, thereaction mixture is poured into ice-cooled water, the aqueous phase isextracted with ethyl acetate, dried and evaporated to dryness underreduced pressure. 38.5 g of the product is obtained in the form of anoil (T_(bp): 230° C. under 10⁻² mbar)

Rf: 0.36 cyclohexane.

IR (CHCl₃)

Aromatic 1569, 1583, 1510, 1493 cm⁻¹

Preparation 5 1-iodo-4-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-benzene

387 mg of imidazole and 411 mg of tertbutyldimethylsilyl chloride isadded at ambient temperature and under an inert atmosphere to 500 mg ofpara-iodo-phenol in 4 ml of dimethylformamide and the mixture ismaintained under agitation for 15 hours at ambient temperature then for1 hour at 40° C. The reaction medium is poured into water, and theaqueous phase is extracted with dichloromethane. The organic phase isthen dried and evaporated under reduced pressure. In this way 636 mg ofexpected product is obtained.

Rf=0.82 cyclohexane/acetate ethyl 9/1).

NMR (CDCl₃) 200 MHz

0.1 p.p.m (s) CH₃ 0.9 p.p.m (s) tBu 6.55 p.p.m (d) to 7.5 p.p.m (d): thearomatic 4H′s

Preparation 6 1-iodo-4-(phenylmethoxy)-benzene

2.4 g of 50% sodium hydride in oil is added at 0° C. and under an inertatmosphere to 10 g of para-iodo-phenol in 150 ml of dimethylformamide,the mixture is maintained under agitation for 30 minutes and 5.9 ml ofbenzyl bromide is added. After agitation for 30 minutes while allowingthe reaction medium to return to ambient temperature, the reactionmedium is poured onto ice and a precipitation of the product isobserved. After drying, 14.7 g of expected product is obtained.

Rf=0.67 cyclohexane/ethyl acetate 9/1).

NMR (CDCl₃) 200 MHz

7.35 (m) aromatic H′s of the benzyl 7.5 (d) 2 H H₂ and H₆ 6.7 (d) 2 H H₃and H₅ 5 (s) CH ₂Ph

Preparation 7 3,5-dibromo-4-[[(trifluoromethyl)sulphonyl]oxy]-benzaldehyde

14.73 ml of triflic anhydride is added, under inert gas and at 0° C., to19.0 g of 3,5-dibromo-4-hydroxy-benzaldehyde in 100 ml of pyridine.Agitation is carried out for 1 hour while allowing the temperature toreturn to ambient, the reaction medium is poured into water and theaqueous phase is extracted with 3 times 150 ml of dichloromethane. Theorganic phases are dried and evaporated to dryness under reducedpressure. 23.83 g of crude product is obtained which is purified byfiltration chromatography using a cyclohexane/ethyl acetate mixture 1/1as eluant. In this way 23.83 g of expected product is obtained. Rf:0.71, cyclohexane/ethyl acetate 1/1. The operation is carried out in anequivalent manner for the preparation of the following triflates ofgeneral formula II

Preparation R₁ R₃ R₂ R₄ R_(5a) Rf C₆H₁₂/AcOEt 8 Me H Me H CHO 0.34 9/1 9H Me iPr H COCH₃ 0.64 7/3 10 iPr H Cl Me COCH₃ 0.44 7/3 11 Cl H OMe HCHO 0.29 8/2 12 Cl H Cl H CHO 0.53 7/3 13 iPr H Cl H CHO 0.35 9/1 14 H HCl H CO₂Me 0.74 7/3 15 CH═CH—CH═CH Cl H CHO 0.75 7/3 16 Cl H CF₃ H CHO0.22 9/1

EXAMPLE 1

2,6-dibromo-4′-hydroxy-(1,1′-biphenyl)-4-carboxaldehyde

Stage A: Coupling

2,6-dibromo-4′-methoxy-(1,1′-biphenyl)-4-carboxaldehyde

50 ml of toluene, 20 ml of ethanol, 6.6 ml of 2M sodium carbonate, 534mg of (4-methoxyphenyl)-boronic acid obtained as in Preparation 1, 245mg of LiCl, 112 mg of Tetrakis (triphenylphosphine)-palladium(0) areadded, under inert gas, to 1.32 g of the triflate obtained inPreparation 7, and agitation is carried out under reflux for 1 hour 30minutes. After dilution with ethyl acetate the organic phase is washedwith 2N soda, then with a saturated solution of NaCl, dried thenevaporated under reduced pressure, followed by purification bychromatography on silica eluting with a cyclohexane-ethyl acetatemixture(98-2) and 89 mg of expected product is obtained.

Rf=0.68 cyclohexane/ethyl acetate (7/3))

NMR (CDCl₃, 300 MHz)

3.88 (s) OCH ₃ 7.01-7.15 (AA′ BB′) Ph—O— 8.12 H₃, H₅ 9.94 (s) CHO

Stage B: Deprotection

2,6-dibromo-4′-hydroxy-(1,1′-biphenyl)-4-carboxaldehyde

15 ml of dichloromethane is added under inert gas to 1.2 g of theproduct prepared in the previous stage, then, at −45° C., 0.75 ml ofBBr3 is added and agitation is carried out for 1 hour at −45° C. thenfor 15 hours while allowing the temperature to evolve from −45° C. to−22° C. After hydrolysis by the addition of a saturated solution ofsodium acetate and extraction with dichloromethane and ethyl acetate,the organic phase is dried and evaporated under reduced pressure. Thecrude reaction product is chromatographed on silica eluting with acyclohexane-ethyl acetate mixture (98-2). In this way 471 mg of expectedproduct is obtained.

Rf=0.28 cyclohexane/ethyl acetate (8/2)

I.R. Nujol

OH/NH absorption ^(˜)3450 cm⁻¹

C═O 1684 cm⁻¹

Aromatic 1611, 1589, 1534, 1518 cm⁻¹

NMR (CDCl₃, 300 MHz)

4.97 (s, OH); 6.95 and 7.20 (AA′BB′, Ph—O); 8.12 (s) H3, H5;

9.94 (s, CHO).

EXAMPLE 2 2,6-dibromo-4′-hydroxy-(1,1′-biphenyl)-4-methanol

140 mg of the product prepared in Example 1 in 3 ml of methanol iscooled down to 0° C., 15 mg of sodium borohydride is added followed byagitation for 1 hour at 0° C. The methanol is evaporated off underreduced pressure and water is added to the residue. The aqueous phase isextracted with ethyl acetate, and the organic phase is evaporated underreduced pressure. The residue is then chromatographed on silica elutingwith a cyclohexane/ethyl acetate mixture 9/1. 47 mg of expected productis obtained.

Rf=0.67 cyclohexane/ethyl acetate (4/6)

I.R. Nujol

Absence of C═O

General absorption OH/NH

Aromatic 1612, 1594, 1518 cm⁻¹

NMR (CDCl₃, 300 MHz)

1.83 (t, OH); 4.71 (d, CH₂); 4.95 (s, OH); 6.92-7.08 (AA′BB′, Ph—O);7.64 (s, H3, H5).

EXAMPLE 3 2-chloro-4′-hydroxy-6-methoxy-(1,1′-biphenyl)-4-methanol

Stage A: Coupling

2-chloro-6-methoxy-4′-phenylmethoxy-(1,1′-biphenyl)-4-carboxaldehyde

1.4 g of potassium bromide, 3.7 g of K3PO4 monohydrate, 2.68 g then 0.55g of the boronic acid obtained in Preparation 2, 0.62 g of Tetrakis(triphenylphosphine)-palladium(0) are added to a solution, under aninert atmosphere, of 3 g of the triflate obtained in Preparation 11 in20 ml of dioxane, and agitation is carried out for 12 hours at 110° C.After filtration then evaporation under reduced pressure, the mixture ischromatographed on silica eluting with a cyclohexane/ethyl acetatemixture 9/1 then 8/2. 762 mg of the expected pure product is obtained.

Rf=0.4 cyclohexane/ethyl acetate 8/2

NMR (CDCl, 250 MHz)

3.82 (s) OCH ₃ 5.11 (s) CH ₂Ph 7.08 and 7.25 AA′ BB′ Ph—O 7.37 and 7.6(2d) J = 2.5 H₃, H₅ 7.3-7.5 (m) H of the benzyl 9.95 (s) CHO

Stage B: Deprotection and Reduction

2-chloro-4′-hydroxy-6-methoxy-(1,1′-biphenyl)-4-methanol

200 mg of the product obtained in the previous stage is mixed at ambienttemperature in 5 ml of ethanol with 60 mg of palladium on carbon at9.5%. The medium is placed under hydrogen atmosphere and agitation iscarried out for 3 hours at 20° C. followed by filtration thenevaporation under reduced pressure in order to obtain 265 mg a brownoil. The mixture is purified by chromatography eluting with acyclohexane/ethyl acetate mixture 8/2, then 7/3 and finally 1/1. 62 mgof expected product is obtained as well as 37 mg of reduced product(R₅=methyl).

Rf=0.1 cyclohexane/ethyl acetate 7/3

NMR (CDCl₃ 250 MHz)

1.74 (t) CH₂OH 4.71 (d) CH ₂OH 3.75 (s) OCH ₃ 4.79 (s) OH 6.9 and 7.16AA′ BB′ Ph—O 6.91 and 7.09 2d H₃, H₅

EXAMPLE 4

2-chloro-4′-hydroxy-6-(1-methylethyl)-(1,1′-biphenyl)-4-methanol

The process is carried out in an equivalent manner to Example 3 Stage Aand B (coupling+deprotection) as in Example 2 (reduction) starting with210.9 mg of the triflate obtained in Preparation 13 and 36 mg ofexpected product is obtained.

Rf=0.32 cyclohexane/ethyl acetate 7/3

NMR (CDCl₃ 300 MHz)

1.09 (d) CH(CH ₃)₂ 2.81 (sept) CH(CH₃)₂ 4.60 (s) CH ₂OH 7.28 (m) H₃, H₅6.88 and 6.94 AA′ BB′ Ph—O

EXAMPLE 5 2-chloro-4′-hydroxy-(1,1′-biphenyl)-4-methanol

Stage A: Coupling

Methyl 2-chloro-4′-phenylmethyloxy-(1,1′-biphenyl)-4-carboxylate

The operation is carried out in an equivalent manner to Example 3 StageA starting with 1.58 g of the triflate obtained in Preparation 14 and0.96 g of expected product is obtained.

Rf=0.42 cyclohexane/ethyl acetate 90/10

NMR (CDCl₃ 300 MHz)

3.95 s CO₂CH ₃ 5.12 s PhCH ₂ 8.13 d H₃ 7.95 dd H₅ 7.30 7.50 m 6 H H ofthe benzyl + H₆ 7.04 and 7.41 AA′ BB′ Ph—O

Stage B: Reduction of the Ester

2-chloro-4′-phenylmethyloxy-(1,1′-biphenyl)-4-methanol

204.4 mg of the ester in 10 ml of tetrahydrofuran and 44 mg of lithiumand aluminium hydride are mixed together for 2 hours, under an inertatmosphere and at 0° C., then the mixture is poured into a saturatedsolution of sodium bicarbonate. After extraction with ethyl acetate,drying and evaporation under reduced pressure, 174 mg of expectedproduct is obtained.

Rf=0.17 cyclohexane/ethyl acetate 8/2.

Stage C: Deprotection

2-chloro-4′-hydroxy-(1,1′-biphenyl)-4-methanol

The operation is carried out in an equivalent manner to Example 3 StageB starting with 174 mg of the benzyl derivative of the previous stageand 55 mg of expected product and 37% of the reduced analogue areobtained (R₅═CH₃,

Rf=0.53 cyclohexane/ethyl acetate 7/3)

Rf=0.18 cyclohexane/ethyl acetate 7/3

NMR DMSO 250 MHz

4.52 s CH ₂OH 5.33 s CH₂OH 7.30 ws 2 H and 7.44 s 1 H H₃, H₅, H₆ 6.84 dand 7.23 d Ph—O 9.59 s Ph—OH

EXAMPLE 6 4′-ethyl-5′-methyl-2′-(1-methylethyl)-(1,1′-biphenyl)-4-ol

The operation is carried out in an equivalent manner to Example 4starting with 1.52 g of the triflate obtained in Preparation 9. Afterpurification by chromatography, eluting with a cyclohexane/ethyl acetatemixture 10/0, 9/1 then 7/3, 100 mg of expected product is obtained whichis recrystallized from pentane, as well as 48 mg of the correspondingalcohol (R₅=CH(OH)CH₃, Rf=0.27).

Rf=0.55 cyclohexane/ethyl acetate: 1/1

M.p.=106-108° C.

NMR (CDCl₃)

1.15 d CH(CH ₃)₂ 1.26 d CH ₂CH₃ 2.66 d CH₂CH ₃ 2.28 s CH ₃ 3.03 dCH(CH₃)₂ 4.71 s OH 6.85 and 7.15 2d Ph—O 7.14 and 6.95 2s H₃′ and H₆′

EXAMPLE 72-chloro-4′-hydroxy-6-(trifluoromethyl)-(1,1′-biphenyl)-4-methanol

The process is carried out in an equivalent manner to Example 3 startingwith 285 mg of the triflate obtained in Preparation 16 and 10.6 mg ofexpected product is obtained.

Rf=0.23 cyclohexane/ethyl acetate: 7/3

NMR (DMSO, 300 MHz)

4.62 d CH ₂OH 5.54 t CH₂OH 6.82 and 6.98 AA′ BB′ Ph-OH 7.72 ws 7.76 wsH₃, H₅ 9.62 s Ph—OH

EXAMPLE 8 3-chloro-4-(4-hydroxyphenyl)-1-naphthalene-methanol

Stage A: Coupling

3-chloro-4-(4-phenylmethoxyphenyl)-1-naphthalene-carboxaldehyde.

The process is carried out in an equivalent manner to Example 3 Stage Astarting with 1.7 g of the triflate obtained in Preparation 15 and 1.1 gof the expected purified product is obtained.

Rf=0.50 cyclohexane/ethyl acetate: 8/2

Infrared spectrum (IR) Solvant: CHCl₃

1693 cm⁻¹ carbonyle

1609, 1576, 1563, 1516, 1506cm⁻¹ aromatics

Stage B: Deprotection

3-chloro-4-(4-hydroxyphenyl)-1-naphthalene-carboxaldehyde (product a)and 3-chloro 4-[4-hydroxy 3-(phenylmethyl) phenyl] 1-naphthalenecarboxaldehyde (product b).

150 mg of the chlorinated derivative of the previous stage and 3 ml oftrifluoroacetic acid are mixed together for 10 minutes under an inertatmosphere. After extraction with ethyl acetate and evaporation underreduced pressure, the crude product is purified by chromatographyeluting with a cyclohexane-dichloromethane/ether mixture 70/20/10. 40mg. of expected product (a) is obtained which is used as it is in thefollowing stage as well as 60 mg of the analogue (b) deprotected andrearranged in position 3 of the phenyl (Rf=0.45 cyclohexane/ethylacetate 70/30).

Rf=0.40 cyclohexane/ethyl acetate: 7/3

Stage C: Reduction

3-chloro-4-(4-hydroxyphenyl)-1-naphthalene-methanol

The process is carried out in an equivalent manner to Example 2,starting with product (a) obtained in the previous stage. 25 mg of theexpected pure product is obtained.

Rf=0.15 cyclohexane/ethyl acetate: 7/3

Microanalysis % found C 71.6 H 4.50 Cl 12.5 % calculated C 71.71 H 4.6Cl 12.45 O 11.24

EXAMPLE 94-[4-hydroxy-3-(phenylmethyl)phenyl]-3-chloro-1-naphthalenemethanol

The operation is carried out in an equivalent manner to Example 3,starting with 60 mg of product (b) obtained in Example 8 Stage B and 40mg of expected product is obtained.

Rf=0.15 (cyclohexane/ethyl acetate 70/30

NMR (CDCl₃)

1.82 CH₂OH

5.18 (s) CH₂OH

4.07 (s) CH ₂Ph

4.82 (s) Ph—OH

6.94 (d1) 1H; 7.10 (m) 2H; 7.15 to 7.47 5H; 7.42 1H; 7.53 2H;

7.69 (s) 1H; 8.09 (d) 1H: Aromatics

EXAMPLE 10 4-(2-chloro-4-methyl-1-naphthalenyl)-phenol

190 mg of the alcohol obtained in Stage C of Example 8, 50 mg ofpalladium on carbon at 9.5 % and 30 ml of ethyl acetate are mixedtogether for 15 minutes under a hydrogen atmosphere at ambienttemperature. After filtration and evaporation under reduced pressure,the crude product is purified by chromatography eluting with acyclohexane/ethyl acetate mixture 95/5. In this way 45 mg of expectedproduct is obtained.

Rf=0.60 (cyclohexane/ethyl acetate)

NMR (CDCl3, 250 MHz)

2.71 s CH ₃

5.14 s Ph—OH

6.98 and 7.20 Ph—OH

7.25 to 7.40, 7.99 dd naphthyl

Microanalysis % found C 75.7 H 5.0 Cl 13.2 % calculated C 75.98 H 4.88Cl 13.19 O 5.95

EXAMPLE 11 2,6-dimethyl-4′-hydroxy-(1,1′-biphenyl)-4-carboxaldehyde

Stage A: Coupling

2,6-dimethyl-4′-[[(1,1-dimethylethyl)diphenylsilyl]oxy](1,1′-biphenyl)-4-carboxaldehyde

1.58 g of LiCl, 600 mg Tetrakis(triphenylphosphine)-palladium(0), 10.56g of [4-[[(1,1-dimethylethyl) diphenylsilyl] oxy]phenyl]-tributyltinobtained in Preparation 4 is added, under inert gas, to 4 g of thetriflate obtained in Preparation 8 in 20 ml of dioxane, and agitation iscarried out at 100° C. for 16 hours. The dioxane is partially evaporatedfollowed by taking up in dichloromethane. The organic phase is washedwith a saturated solution of KF, dried then evaporated under reducedpressure. The residue is purified by chromatography on silica elutingwith a cyclohexane-ethyl acetate mixture (99-01). The expected productis obtained with a yield of 40%.

Rf=0.39 cyclohexane/ethyl acetate (95/5))

IR (CHCl₃)

C═O 1693 cm⁻¹

aromatics 1607, 1591, 1571, 1510 cm⁻¹

Stage B: Deprotection

2,6-dimethyl-4′-hydroxy-(1,1′-biphenyl)-4-carboxaldehyde

35 ml of tetrabutylammonium fluoride is added, under inert gas, to asolution of 1.8 g of the previous product in 10 ml of tetrahydrofuranand agitation is carried out for 10 minutes at ambient temperature.After evaporation of the tetrahydrofuran the crude product thusrecovered is chromatographed on silica eluting with a cyclohexane/ethylacetate mixture (90/10). In this way 634 mg of expected product isobtained.

Rf=0.36 cyclohexane/ethyl acetate 7/3

I.R. CHCl₃

OH 3597 cm⁻¹

C═O 1695 cm⁻¹

aromatics 1613, 1603, 1592, 1568, 1518 cm⁻¹

EXAMPLE 121-[2-chloro-4′-hydroxy-3-methyl-6-(1-methylethyl)-(1,1′-biphenyl-4-yl)]-ethanone

1.63 g of the boronic acid obtained in Preparation 3, 1.42 g oftri-potassium phosphate 1-hydrate, 538 mg of anhydrous potassium bromideand 474 mg of Tetrakis (triphenylphosphine)-palladium (0) are added,under inert gas, to 1.47 g of the triflate obtained in Preparation 10 in30 ml of dioxane. Agitation is carried out at 100° C. for 48 hours, thereaction mixture is filtered and evaporated under reduced pressure untila dry extract is obtained. The crude product thus recovered isredissolved in 20 ml of tetrahydrofuran and 4.5 ml of a 1M solution oftetrabutylammonium bromide is added. After agitation for 2 hours themixture is chromatographed on silica eluting with a cyclohexane/ethylacetate mixture 1/9 then 4/6. 552 mg of expected crude product is thuscollected which is recrystallized from an ether/hexane mixture 1/4. 415mg of expected purified product is obtained.

Rf=0.15 cyclohexane/ethyl acetate 9/1

M.p.=176-7° C.

NMR (CDCl₃) 300 MHz

1.09 (d) CH(CH ₃)₂ 2.48 and 2.61 (2s) COCH₃ and CH₃ 2.75 (m) CH(CH₃)₂4.88 (s) Ph—OH 6.92 and 7.02 (2d) aromatics Ph—O 7.39 (s) aromaticsPh—CO

EXAMPLE 131-[2-chloro-4′-hydroxy-3-methyl-6-(1-methylethyl)-(1,1′-biphenyl-4-yl)]-ethanol

By operating as in Example 2, starting with 220 mg of the productprepared in Example 12 and after purification by chromatography onsilica with a cyclohexane/ethyl acetate mixture 7/3 followed byrecrystallization from ether, 152 mg of expected product is obtained.

Rf=0.32 cyclohexane/ethyl acetate 1/1

M.p.=220-222° C.

NMR (CDCl₃) 300 MHz

1.10 (d) CH(CH ₃)₂ 1.52 d CH(OH)CH ₃ 2.39 s Ph—CH ₃ 2.71 (m) CH(CH₃)₂4.73 s Ph—OH 5.21 m CH(OH)CH₃ 1.77 d CH(OH)CH₃

EXAMPLE 142,6-dichloro-alpha-ethynyl-4′-hydroxy-(1,1′-biphenyl)-4-methanol

Stage A: Coupling

2,6-dichloro-4′-[[(1,1-dimethylethyl)diphenylsilyl]oxy]-(1,1′-biphenyl)-4-carboxaldehyde.

The operation is carried out in an equivalent manner to Example 3starting with 20.2 g of the triflate obtained in Preparation 12 in 125ml of dioxane and 22.4 g of the boronic acid obtained in Preparation 3.After purification by chromatography eluting with acyclohexane/methylene chloride mixture 92/8 then 90/10 and finally80/20, 12.5 g of a mixture constituted by 62% of dichlorinated productand 38% of monochlorinated product.

Rf=0.66 cyclohexane/ethyl acetate 7/3

Stage B: Addition of Magnesium Compound

2,6-dichloro-alpha-ethynyl-4′-[[(1,1-dimethylethyl)diphenylsilyl]oxy]-(1,1′-biphenyl)-4-methanol

1.5 ml of ethynylmagnesium bromide in THF is added at 0-5° C., to asolution under inert gas of 700 mg of the silylated product prepared inthe previous stage in 15 ml of THF, followed by agitation for 2 hours 30minutes at this temperature. After neutralization with saturatedammonium chloride, extraction is carried out with ethyl acetate,followed by drying, filtering and evaporation under reduced pressureuntil 720 mg of expected crude product is obtained.

Stage C: Deprotection of the Silylated Product

2,6-dichloro-alpha-ethynyl-4′-hydroxy-(1,1′-biphenyl)-4-methanol

The operation is carried out in an equivalent manner to Example 11 StageB and 90 mg of purified product is obtained.

Rf=0.36 cyclohexane/ethyl acetate: 1/1

NMR (CDCl₃ 250 MHz)

2.75 (d) CH(OH)—C≡C—H 5.47 (ws, d after exchange) CH(OH)—C≡C—H 2.32 (m)and 4.92 (m) mobile 2 H′s 6.93 and 7.14 AA′ BB′ Ph—O 7.59 (s) H₃; H₅

EXAMPLE 152,6-dichloro-alpha-phenyl-4′-hydroxy-(1,1′-biphenyl)-4-methanol

The operation is carried out in an equivalent manner to Example 14stages B and C by the action of phenyl magnesium bromide on 700 mg ofthe silylated product of Example 14 Stage A and 203 mg of expectedproduct is obtained.

Rf=0.5 cyclohexane/ethyl acetate: 1/1

NMR (CDCl₃ 250 MHz)

5.76 (ws, d after exchange) CH(OH)—Ph 6.17 (mobile d) 6.81 and 7.01 AA′BB′ Ph—O 7.25 (t) H₄ of the phenyl 7.35 (t) H₃, H₅ of the phenyl 7.44(dl) H₂, H₆ of the phenyl 7.5 (s) H₃, H₅ 9.61 mobile s Ph—OH

EXAMPLE 162,6-dichloro-alpha-ethyl-4′-hydroxy-(1,1′-biphenyl)-4-methanol

The operation is carried out in an equivalent manner to Example 14stages B and C by the action of ethyl magnesium bromide on 1.2 g of thesilylated product of Example 14 Stage A, and 21 mg of expected productis obtained.

Rf=0.47 cyclohexane/ethyl acetate: 1/1

NMR (CDCl₃ 250 MHz)

0.87 t CH₂CH ₃ 1.63 m CH ₂CH₃ 4.5 m CHOH 5.39 d CHOH 6.83 and 7.03 AA′BB′ Ph—O 7.45 H₃, H₅ 9.62 s Ph—OH

EXAMPLE 17 3-(2,6-dichloro-4′-hydroxy-(1,1′-biphenyl)-4-yl)-2-propenol

Stage A: Homologation by Phosphine

3-(2,6-dichloro-4′-[[(1,1-dimethylethyl)diphenylsilyl]oxy](1,1′-biphenyl)-4-propenal

1.03 g of triphenylphosphine (Φ₃P═CH—CHO) is added to a solution underinert gas of 1.7 g of the silylated product prepared in Example 14 StageA, in 1.5 ml of chloroform, and the reaction medium is taken to refluxfor 6 hours at 120° C. After cooling down, filtering and evaporationunder reduced pressure, the crude product obtained is purified bychromatography, eluting with a cyclohexane/ethyl acetate mixture 9/1.980 mg of expected product is obtained.

Stage B: Reduction of the Aldehyde

3-(2,6-dichloro-4′-[[(1,1-dimethylethyl)diphenylsilyl]oxy](1,1′-biphenyl)-4-propenol

The homologous silylated product obtained in the previous stage isdissolved in 10 ml of methanol. 35 mg of sodium borohydride is addedfollowed by agitation for 1 hour at ambient temperature under an inertatmosphere. The solution is used as it is in the following stage.

Stage C: Deprotection of the Silylated Derivative

3-(2,6-dichloro-4′-hydroxy-(1,1′-biphenyl)-4-yl)-2-propenol

3.5 ml of TBAF is added to the previous solution and the mixture isagitated under an inert atmosphere for 15 minutes. After treatment witha 6N hydrochloric acid solution, extraction with ethyl acetate, dryingof the organic phases and evaporation under reduced pressure, 730 mg ofexpected crude product is obtained which is purified by chromatographyeluting with a cyclohexane/ethyl acetate mixture 9/1 then 1/1. 1.27 mgof expected pure product is obtained.

Rf=0.24 cyclohexane/ethyl acetate 1/1

NMR (CDCl₃)

1.51 (t, mobile) CH═CH—CH₂—OH 4.37 (m, d after exchange) CH═CH—CH ₂—OH4.85 mobile s Ph—OH 6.41 dt J = 16 CH═CH—CH ₂—OH 6.56 wd J = 16CH═CH—CH₂—OH 6.92 and 7.15 AA′ BB′ Ph—O 7.4 s H₃, H₅

EXAMPLE 18 2-bromo-4′-hydroxy-6-nitro-(1,1′-biphenyl)-4-methanol

Stage A: Coupling

Methyl 2,6-dinitro-4′-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-(1,1′-biphenyl)-4-carboxylate

1.53 g of methyl 4-chloro-3,5-dinitro benzoate obtained in Example 30Stage A in 15 ml of tetrahydrofuran is mixed under an inert atmospherewith 1.96 g of the product of Preparation 5 and 2.8 g of copper, thenagitation is carried out for 24 hours at 120° C. After filtration,evaporation is carried out under reduced pressure and the crude productis purified by chromatography eluting with a cyclohexane/ethyl acetatemixture 9/1 then 1/1. In this way 1.2g of expected product is obtained(Rf=0.45 cyclohexane/ethyl acetate 7/3)

IR (CHCl₃)

C═O 1735cm⁻¹

Aromatics+NO₂: 1620, 1607, 1575, 1545, 1517 cm⁻¹

Stage B: Reduction of the Nitro Group

Methyl2-amino-4′-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-(1,1′-biphenyl)-6-nitro-4-carboxylate

The mixture constituted by 1.15 g of the product obtained in theprevious stage, 4.9 ml of cyclohexene and 345 mg of Pd(OH)₂ is agitatedfor 16 hours under an inert atmosphere, under reflux. After filtrationthen evaporation under reduced pressure, the crude product is purifiedby chromatography eluting with a cyclohexane/ethyl acetate mixture 9/1.670 mg of an oil is obtained which is crystallized from an ethylether/hexane mixture. In this way 522 mg of expected product isobtained.

Rf=0.2 cyclohexane/ethyl acetate 85/15

IR (CHCl₃)

═C—NH₂ 3500 cm⁻¹ C═O 1726 cm⁻¹ Aromatics 1621 cm⁻¹ 1st band NO₂ 1610cm⁻¹ NH₂ 1635, 1516 cm⁻¹

Stage C: Substitution of NH₂ by Br

Methyl2-bromo-4′-[[((1,1-dimethylethyl)dimethylsilyl]oxy]-(1,1′-biphenyl)-6-nitro-4-carboxylate

0.062 ml of terbutylnitrite is added under an inert atmosphere to amixture cooled down to −5° C., constituted by the product of theprevious stage in 1.3 ml of tribromomethyl. After agitation for 15minutes at 100° C., the reaction medium is evaporated under reducedpressure and the crude reaction product is purified by chromatographyeluting with a cyclohexane/ethyl acetate mixture 95/05. In this way 81mg of the expected pure product is obtained.

Rf=0.33 cyclohexane/ ethyl acetate 9/1

IR (CHCl₃)

Absence of ═C—NH₂

C═O 17.30, 1436 cm⁻¹ Aromatic 1608, 1572 cm⁻¹ 1st band NO₂ 1537, 1516cm⁻¹

Stage D: Deprotection

Methyl 2-bromo-4′-hydroxy-6-nitro-(1,1′-biphenyl)-4-carboxylate

The operation is carried out in an equivalent manner to Example 11 StageB starting with the product obtained in the previous stage. 279 mg ofthe desilylated product is obtained which is used as it is in thefollowing stage.

Rf=0.38 cyclohexane/ethyl acetate: 9/1

Stage E: Reduction

2-bromo-4′-hydroxy-6-nitro-(1,1′-biphenyl)-4-methanol

The operation is carried out in an equivalent manner to Example 5 StageB starting with 110 mg of the product prepared in the previous stage. Inthis way 85 mg of expected product is obtained which is recrystallizedfrom ethyl ether.

Rf=0.18 cyclohexane/ethyl acetate: 7/3

Microanalysis % found C 48.2 H 2.9 N 4.1 Br 24.8 % calculated C 48.2 H3.1 N 4.3 Br 24.7

EXAMPLE 19

2-amino-6-bromo-4′-hydroxy-(1,1′-biphenyl)-4-methanol

Stage A: Reduction NO₂+Deprotection

Methyl 2-amino-6-bromo-4′-hydroxy-(1,1′-biphenyl)-4-carboxylate

The process is carried out in an equivalent manner to Example 18 Stage Bstarting with 10 g of the product obtained in Stage C of the sameexample. 7.97 g of expected product (reduced and deprotected) and 577 mgof the protected analogue are obtained (Rf=0.56 cyclohexane/ethylacetate 7/3).

Rf=0.17 cyclohexane/ethyl acetate 7/3

Stage B: Reduction of the Ester

2-amino-6-bromo-4′-hydroxy-(1,1′-biphenyl)-4-methanol

The operation is carried out in an equivalent manner to Example 5 StageB starting with 550 mg of the product obtained in the previous stage.250 mg of expected product is obtained.

Rf=0.18 cyclohexane/ethyl acetate 7/3

Microanalysis % found C 52.8 H 4.1 N 4.5 Br 26.9 % calculated C 53.1 H4.1 N 4.8 Br 27.2

IR (Nujol)

Absence of C═O

OH/NH absorption

Aromatic region, NH₂: 1606, 1586, 1550, 1540, 1516, 1496 cm⁻¹

EXAMPLE 20 2-bromo-4′-hydroxy-6-methylthio-(1,1′-biphenyl)-4-methanol

Stage A: Substitution of NH₂ by SMe

Methyl2-bromo-4′-[[(1,1-dimethylethyl)diphenylsilyl]oxy]-6-methylthio-(1,1′-biphenyl)-4-carboxylate

The mixture constituted by 400 mg of the product prepared in Example 19Stage A (reduced and protected product) in 1 ml of chloroform, 0.17 mlof (CH₃S)₂ and 0.16 ml of terbutylnitrite is agitated for 16 hours underan inert atmosphere at ambient temperature. After hydrolysis of thereaction medium, extraction and concentration under reduced pressure,the crude product is purified by chromatography eluting with acyclohexane/ethyl acetate mixture 998/02. In this way 245 mg of expectedproduct is obtained.

Rf=0.47 cyclohexane/ethyl acetate 1/1

NMR (CDCl, 200 MHz)

0.19 s Si(CH ₃)₂ 0.9 s Si—C(CH₃)₃ 2.3 s S—CH ₃ 6.85 and 7.0 AA′ BB′ Ph—O7.68 d and 8.0 d H₃, H₅

Stage B: Reduction+Deprotection

2-bromo-4′-hydroxy-6-methylthio-(1,1′-biphenyl)-4-methanol

The operation is carried out in an equivalent manner to Example 18stages D and E starting with 200 mg of the product obtained in theprevious stage. 10.9 mg of expected pure product is thus obtained.

Rf=0.2 cyclohexane/ethyl acetate 7/3

NMR (DMSO, 250 MHz)

2.31 s S—CH ₃ 4.53 s CH ₂OH 5.34 (t, mobile) CH₂OH 6.81 and 6.93 AA′ BB′Ph—O 7.17 (ws) and 7.39 (ws) H₃, H₅ 9.54 (s, l) Ph—OH

EXAMPLE 212-bromo-4′-hydroxy-6-(1H-pyrrol-1-yl)-(1,1′-biphenyl)-4-methanol

Stage A: Formation of the Pyrrol Starting with the Amine

Methyl2-bromo-4′-[[(1,1-dimethylethyl)diphenylsilyl]oxy]-6-(1H-pyrrol-1-yl)-(1,1′-biphenyl)-4-carboxylate

700 mg of the product prepared in Example 19 (reduced and protectedproduct) in 17 ml of acetic acid and 23 ml of 2,6-dimethoxytetrahydrofuran are mixed under an inert atmosphere and taken to refluxfor 16 hours. After hydrolysis of the reaction medium, extraction withethyl acetate and evaporation under reduced pressure, 813 mg of expectedcrude product is obtained which is used as it is for the followingstage.

Rf=0.8 cyclohexane/ethyl acetate

NMR (CDCl₃, 200 MHz)

0.12 s Si(CH ₃)₂ 0.85 s Si—C(CH ₃)₃ 3.85 s CO₂CH ₃ 5.95 m H₃, H₄ of thepyrrol 6.56 m H₂, H₅ of the pyrrol 6.66 and 6.87 AA′ BB′ Ph—O 7.31 and7.67 H₃, H₅

Stage B: Reduction and Deprotection

2-bromo-4′-hydroxy-6-(1H-pyrrol-1-yl)-(1,1′-biphenyl)-4-methanol

The operation is carried out in an equivalent manner to Example 18stages D and E starting with 750 mg of the product obtained in theprevious stage. In this way 212 mg of expected pure product is obtained.

Rf=0.29 cyclohexane/ethyl acetate 7/3

NMR (DMSO, 250 MHz)

5.42 t, mobile CH₂OH 4.57 d, s after exchange CH ₂OH 5.95 m H₃, H₄ ofthe pyrrol 6.56 m H₂, H₅ of the pyrrol 6.66 and 6.87 AA′ BB′ Ph—OH 7.31and 7.67 d H₃, H₅ 9.44 s mobile Ph—OH

EXAMPLE 22 2,6-dimethoxy-4′-hydroxy-(1,1′-biphenyl)-4-methanol

Stage A: Coupling

2,6-dimethoxy-4′-benzyloxy-(1,1′-biphenyl)-4-carboxaldehyde

19 g of the boronic acid obtained in Preparation 2, 7.15 g oftripotassium phosphate 1-hydrate and 1.2 g of Tetrakis(triphenylphosphine)-palladium(0) are added, under inert gas, to 5.07 gof 4-bromo-3,5-dimethoxy-benzaldehyde (Finorga) in 50 ml of dioxane. Thereaction mixture is taken to reflux for 15 hours, poured into ice-cooledwater and the aqueous phase is extracted with ether then ethyl acetate.The organic phases are dried and evaporated under reduced pressure. Thecrude product thus recovered is chromatographed on silica eluting with adichloromethane/pentane mixture 70/30. In this way 2.84 g of expectedproduct is collected.

Rf=0.5 dichloromethane

I.R. CHCl₃

C═O 1692 cm⁻¹ Aromatics 1610, 1582, 1572, 1520, 1499 cm⁻¹

Stage B: Debenzylation and Reduction

2,6-dimethoxy-4′-hydroxy-(1,1′-biphenyl)-4-methanol

502.3 mg of the product obtained in the previous stage in 13 ml of ethylacetate is mixed at ambient temperature with 161 mg of palladium oncarbon at 9.5%. The reaction medium is placed under a hydrogenatmosphere and agitation is carried out for 3 hours. After filtration,the filtrate is evaporated under reduced pressure and the crude residueis chromatographed on silica eluting first with dichloromethane thenwith a dichloromethane/methanol mixture 95/5. In this way 134 mg ofexpected product is collected as well as 110 mg of the product ofExample 23 (R₅=Me).

Rf=0.41 dichloromethane/methanol 9/1

M.p.=184° C.

I.R. Nujol

Absence of C═O OH/NH region max 3500 cm⁻¹ max 3260 cm⁻¹ Aromatics 1610,1593, 1579, 1523, 1492 cm⁻¹

EXAMPLE 23

2′,6′-dimethoxy-4′-methyl-(1,1′-biphenyl)-4-ol

106.5 mg of the product obtained in Stage A of Example 22 in 3.5 ml ofethyl acetate is mixed at ambient temperature with 34 mg of palladium oncarbon at 9.5%. The reaction medium is placed under a hydrogenatmosphere and agitation is carried out for 24 hours at 20° C. Afterfiltration, the mixture is evaporated under reduced pressure and in thisway 69 mg of expected product is collected.

Rf=0.45 cyclohexane/ethyl acetate 7/3

M.p.=162° C.

I.R. Nujol

Absence of C═O —OH 3598 cm⁻¹ Aromatics 1606, 1592, 1575, 1521, 1489 cm⁻¹

EXAMPLE 24 2,6-dichloro-4′-hydroxy-(1,1′-biphenyl)-4-methanol

Stage A: Protection

2-(3,5-dichlorophenyl)-1,3-dioxolane

4.66 g of 3,5-dichlorobenzaldehyde is mixed with 0.23 g ofparatoluenesulphonic acid, 3 ml of ethylene glycol and 40 ml of toluene.The reaction medium is heated under reflux for 2 hours, poured into asaturated solution of sodium bicarbonate and the aqueous phase isdecanted. The organic phase is dried and evaporated under reducedpressure. 5.756 g of expected product is isolated in the form of an oil.

Rf=0.45 cyclohexane/ethyl acetate 9/1.

I.R. CHCl₃

Absence of C═O Aromatics 1592, 1575 cm⁻¹

Ketal

Stage B: Orthometallation and Iodation

2-(3,5-dichloro-4-iodo phenyl)-1,3-dioxolane

A solution of 5.631 g of the product obtained in the previous stage in45 ml of tetrahydrofuran is cooled down to −78° C. under an inertatmosphere, 21.4 ml of a solution of n-butyllithium is added dropwiseover 1 hour, the mixture is agitated at −78° C. for 30 minutes, then asolution of 6.94 g of N-iodosuccinimide in 40 ml of tetrahydrofuran isadded dropwise over 1 hour. Agitation is carried out for 1 hour at −78°C., the reaction mixture is poured into a saturated solution of ammoniumchloride and extracted with methylene chloride. The organic phase isdried and evaporated under reduced pressure. 10.11 g of expected productis isolated in the form of an oil.

Rf=0.22 cyclohexane/ethyl acetate 95/5.

Stage C: Coupling

2-[2,6-dichloro-4′-phenylmethoxy-(1,1′-biphenyl)-4-yl]-1,3-dioxolane

10.11 g of the product obtained in the previous stage is mixed with 60ml of toluene, 10.69 g of boronic acid (Preparation 2), 29.3 ml of asolution (2M) of sodium carbonate, 15 ml of ethanol and 1.69 g ofTetrakis (triphenylphosphine)-palladium (0). Agitation is carried outunder toluene reflux under an inert atmosphere for 15 hours and thereaction mixture is poured into a saturated solution of sodiumbicarbonate and extracted with ether. The organic phase is washed with asaturated solution of ammonium chloride, then with a solution of sodiumchloride, dried and evaporated under reduced pressure. 14.43 g ofexpected product is isolated in the form of an oil.

Rf=0.2 cyclohexane/ethyl acetate 90/10.

I.R. CHCl₃

Aromatics 1611, 1580, 1555, 1520, 1498 cm⁻¹

Stage D: Deprotection (Hydrolysis of Ketal)

2,6-dichloro-4′-phenylmethoxy-(1,1′-biphenyl)-4-carboxaldehyde

14.31 g of the product obtained in the previous stage is mixed with 70ml of tetrahydrofuran and 36 ml of 1N hydrochloric acid. The reactionmixture is heated under tetrahydrofuran reflux for 15 hours and treatedwith a saturated solution of sodium bicarbonate and the aqueous phase isextracted with dichloromethane. The organic phase is dried andevaporated under reduced pressure. 13.24 g of crude product in the formof an oil is chromatographyed on silica eluting with a cyclohexane/ethylacetate mixture 99.5/0.5. In this way 2.352 g of expected product isobtained.

Rf=0.4 cyclohexane/ethyl acetate 90/10

I.R. CHCl3

Aromatics 1609, 1590, 1577, 1548, 1516 cm⁻¹

C═O 1707 cm⁻¹

Stage E: Debenzylation

2,6-dichloro-4′-hydroxy-(1,1′-biphenyl)-4-methanol

101.4 mg of the product obtained in the previous stage in 5 ml ethylacetate is mixed at ambient temperature with 31 mg of palladium oncarbon at 9.5%. The reaction medium is placed under a hydrogenatmosphere and agitation is carried out for 4 hours at 20° C. Afterfiltration, the filtrate is evaporated under reduced pressure thenpurified by chromatography on silica eluting with a cyclohexane/ethylacetate mixture 9/1. In this way 61 mg of expected product is collected.

Rf=0.21 cyclohexane/ethyl acetate 7/3

M.p.=161° C.

I.R. CHCl₃

—OH 3599 cm⁻¹

Aromatics 1613, 1603, 1593, 1546, 1520, 1501 cm⁻¹

EXAMPLE 25 2,6-dichloro-4′-hydroxy-(1,1′-biphenyl)-4-carboxaldehyde

The mixture constituted by 101.6 mg of the product prepared in Stage Dof Example 24 in 1 ml of dichloromethane and 0.053 ml of trimethylsilyliodide is agitated for 1 hour at 25° C. under an inert atmosphere. Afterhydrolysis with methanol and evaporation under reduced pressure, theresidue is taken up in dichloromethane, washed with water, the organicphase is dried and evaporated under reduced pressure. The crude productobtained is purified by chromatography eluting with a cyclohexane/ethylacetate mixture 95/5. 50 mg of expected pure product is obtained.

M.p.=154-156° C.

Rf=0.21 cyclohexane/ethyl acetate 8/2

NMR (DMSO 300 MHz)

6.88 d and 7.10 AA′ BB′ Ph—OH 8.04 s 2 H H₃, H₅ 9.77 s Ph—OH 10.00 s CHO

EXAMPLE 26 4′-hydroxy-2.3,5,6-tetrachloro-(1,1′-biphenyl)-4-methanol

Stage A: Coupling

4′-phenylmethoxy-2,3,5,6-tetrachloro-(1,1′-biphenyl)

1 g of 3-iodo-1,2,4,5-tetrachlorobenzene, 790 mg of the boronic acidobtained in Preparation 2, 80 mg of palladium tetrakis and 1 g ofpotassium phosphate in 100 ml of dioxane are mixed together. Thereaction medium is taken to reflux for 5 hours, another 80 mg ofpalladium tetrakis is added and the reaction medium taken to reflux for24 hours. The mixture is chromatographed directly on silica eluting witha cyclohexane/ethyl acetate mixture 99/1. In this way 689 mg of crudeproduct is collected, which is recrystallized from an ether-pentanemixture. The expected product is obtained with a yield of 60%.

Rf=0.6 cyclohexane/ethyl acetate 95/5

I.R. CHCl₃

Aromatics : 1601, 1590, 1500 cm⁻¹

Stage B: Formylation

4′-phenylmethoxy-2,3,5,6-tetrachloro-(1,1′-biphenyl)-4-carboxaldehyde

350 mg of the product prepared in the previous stage in 5 ml oftetrahydrofuran is cooled down to −78° C., 0.69 ml of a 1.45M solutionof n-butyllithium in hexane is added dropwise then after agitation for 2hours at −78° C. 90 μl of dimethylformamide in 0.4 ml of tetrahydrofuranis added dropwise. Agitation is carried out for 16 hours at −65° C., thereaction medium is poured into 13.6 g of ice and 2.7 ml of concentratedhydrochloric acid and the aqueous phase is extracted with ethyl acetate.After drying and concentration 320 mg of a mixture is obtained composedof the expected product and the starting product which is used directlyin the following stage.

Rf=0.47 cyclohexane/ethyl acetate 95/5

NMR (CDCl₃) 200 MHz

10.35 (s) CHO 7 (m) Ph—O aromatic H′s 7.4 (m) benzyl aromatic H′s 5.05(s) Ph—CH ₂—O

Stage C: Reduction

4′-phenylmethoxy-2,3,5,6-tetrachloro-(1,1′-biphenyl)-4-methanol

320 mg of the product prepared in the previous stage is mixed with 16 mlof methanol, 34 mg of sodium borohydride and 0.5 ml of dichloromethaneand the reaction medium is agitated for 15 minutes at ambienttemperature. The reaction mixture is then poured into a saturatedsolution of ammonium chloride, the aqueous phase is extracted with ethylacetate, dried and evaporated under reduced pressure. The residue ischromatographed on silica eluting with an ethyl acetate/cyclohexanemixture 10/90. In this way 130 mg of expected product is obtained.

Rf=0.56 cyclohexane/ethyl acetate 95/5.

Stage D: Deprotection

4′-hydroxy-2.3,5,6-tetrachloro-(1,1′-biphenyl)-4-methanol

130 mg of the product obtained in the previous stage in 5.5 ml of ethylacetate is mixed at ambient temperature with 34 mg of palladium oncarbon at 9.5%. The reaction medium is placed under a hydrogenatmosphere and agitation is carried out for 6 hours at 20° C. Afterfiltration, the filtrate is evaporated under reduced pressure thenpurified by chromatography on silica eluting with a cyclohexane/ethylacetate mixture 9/1. In this way 116 mg of crude product is collectedwhich is recrystallized from dichloromethane. 47 mg of expected productis obtained.

Rf=0.14 cyclohexane/ethyl acetate 8/2

NMR (CD₃COCD₃) 250 MHz

2.23 (m) CH₂OH 4.97 wide Ph—OH 5.13 (s) CH ₂OH 7.10, 6.96 (dd) Ph—OHaromatic H′s

EXAMPLE 27 2,6-difluoro-4′-hydroxy-(1,1′-biphenyl)-4-methanol

Stage A: Protection

1,3-difluoro 5-[(tetrahydropyrannyloxy)methyl]-benzene

1.286 g of 3,5-difluorophenyl methanol is mixed under an inertatmosphere with 1.3 ml of 3,4-dihydropyranne, 155 mg ofparatoluenesulphonic acid and 20 ml of dioxane and agitation is carriedout at 20° C. for 2 hours 30 minutes. The reaction mixture is pouredinto a saturated solution of sodium bicarbonate, the dioxane isevaporated off under reduced pressure and the aqueous phase is extractedwith ethyl acetate. The organic phase is dried then evaporated underreduced pressure. 1.81 g of expected product is collected.

Rf=0.42 cyclohexane/ethyl acetate 9/1

I.R. CHCl₃

Absence OH

Aromatics 1632, 1602 cm⁻¹

Stage B: Chlorination, Coupling and Deprotection of the Alcohol

2,6-difluoro-4′-phenylmethoxy-(1,1′-biphenyl)-4-methanol

A solution of 1.04 g of the product obtained in the previous stage in 20ml of tetrahydrofuran is cooled down to −78° C. and 3.7 ml of a solutionof n-Butyllithium (1.5M in hexane) is added dropwise under an inertatmosphere then, after agitation for 15 minutes at −78° C., 5.5 ml of asolution of zinc chloride (1.0M in tetrahydrofuran) is added. Afteragitation for 30 minutes at −78° C., the temperature is allowed toreturn to 20° C. and 1.44 g of the product obtained in Stage A ofPreparation 2 and 265 mg of Tetrakis (triphenyl phosphine)-palladium (0)is added. The reaction mixture is taken to reflux for 5 hours, pouredinto a saturated solution of ammonium chloride and the aqueous phase isextracted with dichloromethane. The organic phase is dried andconcentrated under reduced pressure. The crude product in the form of anoil is used as it is in the following stage of deprotection of thealcohol.

The crude oil is dissolved in 30 ml of methanol and 2.3 ml of 2Nhydrochloric acid is added. The reaction medium is agitated for 4 hoursat 20° C. and poured into a saturated solution of sodium bicarbonate.After concentration of the methanol under reduced pressure, the aqueousphase is extracted with dichloromethane, the organic phase is dried andconcentrated under reduced pressure. In this way 1.851 g of expectedproduct is obtained.

Rf=0.32 cyclohexane/ethyl acetate 7/3

I.R. Nujol

Complex Absorption OH/NH Region

Aromatics 1640, 1612, 1582.1569, 1528, 1492 cm⁻¹

Stage C: Debenzylation

2,6-difluoro-4′-hydroxy-(1,1′-biphenyl)-4-methanol

32 mg of the product obtained in the previous stage in 5 ml of ethylacetate is mixed at ambient temperature with 31 mg of palladium oncarbon at 9.5%. The reaction medium is placed under hydrogen atmosphereand agitation is carried out for 28 hours at 20° C. After filtration,the filtrate is evaporated under reduced pressure. In this way 116 mg ofcrude product is collected which is recrystallized from dichloromethane.18 mg of expected product is obtained.

Rf=0.18 cyclohexane/ethyl acetate 7/3

I.R. Nujol

Complex Absorption OH/NH Region

Aromatics 1636, 1615, 1598.1573, 1530 cm⁻¹

EXAMPLE 28 4′-hydroxy-2-trifluoromethyl-(1,1′-biphenyl)-4-methanol

Stage A: Coupling

4′-benzyloxy-2-trifluoromethyl-(1,1′-biphenyl)-4-carboxaldehyde

By operating as in Example 22 Stage A, starting with 0.911 g of(3-trifluoromethyl-4-bromo-benzaldehyde) and after purification bychromatography on a silica column eluting with a cyclohexane/ethylacetate mixture 95/5, 1.093 g of expected product is obtained.

Rf=0.33 cyclohexane/ethyl acetate (8/2)

I.R. (CHCl₃)

CHO 2736, 1706 cm⁻¹

Ar 1611 (F), 1580, 1565 (sh.) and 1520 cm⁻¹

Stage B: Deprotection and Reduction

4′-hydroxy-2-trifluoromethyl-(1,1′-biphenyl)-4-methanol

308 mg of the product obtained in the previous stage in 15 ml of ethylacetate is mixed at ambient temperature with 290 mg of palladium oncarbon at 9.5%. The reaction medium is placed under a hydrogenatmosphere and agitation is carried out for 12 hours at 20° C. Afterfiltration, the filtrate is evaporated under reduced pressure. 215.7 mgof a mixture of debenzylated product and its reduced analogue isobtained which is used directly in the following reaction.

215.7 mg of the mixture prepared in the previous stage is mixed with 3ml of methanol, 48 mg of sodium borohydride at 95% and agitation iscarried out for 3 hours at ambient temperature. After concentrationunder reduced pressure, the reaction mixture is taken up indichloromethane and washed with a saturated solution of ammoniumchloride, dried and evaporated under reduced pressure. The crudereaction product is chromatographed on silica eluting with an ethylacetate/cyclohexane mixture 2/8. In this way 99 g of expected product isobtained.

Rf=0.20 cyclohexane/ethyl acetate 7/3)

I.R. (Nujol)

Absence of C═O

General Absorption OH/NH Region

1615, 1600, 1520 (sh.) and 1492 cm⁻¹ Ar

EXAMPLE 29 4′-methyl-2′-trifluoromethyl-(1,1′-biphenyl)-4-ol

The operation is carried out as in Example 3 starting with 1.004 g ofthe biphenyl obtained in Stage A of the previous example and 216 mg ofexpected product is obtained as well as 373 mg of the product of Example28 (R₅═CH₂OH)

Rf=0.49 cyclohexane/ethyl acetate 7/3

NMR CDCl₃/250 MHz

2.44 (s) CH ₃ 7.19 (masked) H′₆ 7.34 (dm) H′₅ 7.53 (m) H′₃ 6.85 and 7.20AA′ BB′ Ph—O— 4.74 (s) mobile 1 H

EXAMPLE 30 2,6-dinitro-4′-hydroxy-(1,1′-biphenyl)-4-methanol

Stage A: Esterification

Methyl 4-chloro-3,5-dinitro-benzoate

2.96 ml of SOC1₂ is added at 0° C., under an inert atmosphere anddropwise to 10 g of 3,5-dinitro-4-chlorobenzoic acid (JANSSEN) in 150 mlof methanol and agitation is carried out under reflux of methanol for 2hours then for 15 hours at ambient temperature. The reaction medium ispoured into ice and precipitation of the product is observed. Afterdrying, 10.3 g of expected product is obtained.

Rf=0.45 cyclohexane/ethyl acetate 7/3

I.R. CHCl₃

C═O 1738 cm⁻¹ Aromatics + NO2 1614, 1552 cm⁻¹

Stage B: Coupling

Methyl 2,6-dinitro-4′-phenylmethoxy-(1,1′-biphenyl)-4-carboxylate

10 g of the product of the previous stage in 100 ml of dimethylformamideis mixed under an inert atmosphere with 8.4 g of the product ofPreparation 6 and 15.12 g of copper then agitation is carried out whilebringing the temperature from 20 to 120° C. over 2 hours and maintainingfor 30 minutes at 120° C. After filtration of the crude reactionproduct, the reaction medium is poured into a mixture of ice plus waterand extracted with dichloromethane. The organic phase is dried,concentrated under reduced pressure and chromatographed on silicaeluting with a cyclohexane/ethyl acetate mixture 8/2. In this way 9.1 gof expected product is obtained.

Rf=0.46 cyclohexane/ethyl acetate 7/3

NMR CDCl₃/200 MHz

4 (s) COOMe 7-7.15 Ph—O 7.35 Ph—CH₂—O 8.5 2 H ortho of COOMe 5 Ph—CH ₂—O

Stage C: Deprotection

Methyl 2,6-dinitro 4′-hydroxy (1,1′-biphenyl) 4-carboxylate

11 ml of trifluoroacetic acid is added to 1.3 g of the product obtainedin the previous stage and agitation is carried out under reflux ofacetic acid for 1 hour 30 minutes. The reaction medium is poured onto amixture of ice plus water and extracted with dichloromethane. Theorganic phase is dried, concentrated under reduced pressure andchromatographed on silica eluting with a cyclohexane/ethyl acetatemixture 7/3. In this 330 mg of expected product is collected.

Rf=0.42 cyclohexane/ethyl acetate (7/3)

NMR CDCl₃/200 MHz

3.98 (s) COOMe 6.8-7.1 aromatic 4H′s 8.49 2 H ortho of COOMe

Stage D: Reduction

2,6-dinitro-4′-hydroxy-(1,1′-biphenyl)-4-methanol

The process is carried out in an equivalent manner to Example 5 Stage Bstarting with 330 mg of the product prepared in the previous stage.After purification by chromatography on silica eluting with acyclohexane/ethyl acetate mixture 7/3, 71.8 mg of expected product isobtained.,

Rf=0.45 cyclohexane/ethyl acetate 7/3

M.p.=156-158° C.

NMR DMSO/250 MHz

4.69 (d) Ph—CH ₂OH 5.73 (t) Ph—CH₂OH 6.81 and 7.05 AA′ BB′ Ph—O— 8.15(s) H₃, H₅ 9.82 (s) mobile 1 H

EXAMPLE 31 2-amino-4′-hydroxy-6-nitro-(1,1′-biphenyl)-4-methanol

300 mg of the product prepared in Example 30 in 6 ml of tetrahydrofuranis mixed under an inert atmosphere with 0.64 ml of cyclohexene and 30 mgof Pd(OH)2 and agitation is carried out for 3 hours at ambienttemperature then for 16 hours under reflux of tetrahydrofuran. Afterfiltration the tetrahydrofuran is evaporated off, the reaction medium istaken up in ethyl acetate and the organic phase is extracted with 2Nhydrochloric acid. The acid phase is adjusted to basic pH with 2N soda,then is extracted with ethyl acetate. The organic phase is dried andconcentrated under reduced pressure. The crude product thus obtained isrecrystallized from chloroform. In this way 26 mg of expected product isobtained.

Rf=0.11 dichloromethane/methanol 95/05)

M.p.=158° C.

NMR DMSO/250 MHz

4.44 (ws) Ph—CH ₂OH 5.02 (ws) NH₂ 5.30 (ws) mobile H 5.73 (t) Ph—CH₂OH6.83 (d) and 6.98 (d) 6.91 (ws) and 6.93 (ws) H₃, H₅ CH₂OH 9.57 (s)mobile 1 H

EXAMPLE 32 2-bromo-4′-hydroxy-6-iodo-(1,1′-biphenyl)-4-methanol

Stage A: Iodation of Aminated Biphenyl

Methyl2-bromo-4′-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-6-iodo-(1,1′-biphenyl)-4-carboxylate

4 g of iodine is added to a solution of 2.69 g of the product preparedin Stage A of Example 19, in 50 ml of chloroform, then, dropwise, 1.05ml of terbutylnitrite is added and the reaction medium left underagitation under reflux for 1 hour 30 minutes. After the excess iodine isneutralized with a solution of sodium thiosulphate, the reaction mediumis extracted with chloroform, dried and evaporated under reducedpressure. The crude product is purified by chromatography on a columneluting with a cyclohexane/ethyl acetate mixture 99/1. 3.075 g ofexpected product is obtained.

Rf=0.70 cyclohexane/ethyl acetate 80/20

NMR CDCl₃ 250 MHz

0.25 s Si(CH ₃)₂ 1.01 s Si—C(CH ₃)₃ 3.94 s CO₂CH ₃ 6.96 AA′ BB′ Ph—O8.29 d and 8.52 d H₃, H₅

Stage B: Reduction

2-bromo-4′-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-6-iodo-(1,1′-biphenyl)-4-methanol

2 equivalents of an extemporaneous solution ofdiisobutylaluminium/nbutyl lithium/toluene/n-hexane is added under aninert atmosphere at −70° C., to a solution of 160 mg of the esterprepared in the previous stage in 2 ml of toluene, agitation is carriedout for 3 hours at −70° C. and 19.4 mg of sodium borohydride in 0.5 mlof methanol is added. After agitation for 45 minutes outside the icebath, the reaction medium is poured into ice-cooled water then extractedwith ethyl acetate. After drying, then evaporation under reducedpressure, the crude product obtained is purified by chromatographyeluting with a cyclohexane/ethyl acetate mixture 98/2 then 95/5. 141 mgof expected product is obtained which is used as it is in the followingstage.

Rf=0.48 cycohexane/ethyl acetate 7/3

Stage C: Deprotection of the Phenol

2-bromo-4′-hydroxy-6-iodo-(1,1′-biphenyl)-4-methanol

The operation is carried out in the same manner as in Example 11 Stage Bstarting with 141 mg of the product obtained in the previous stage. 81mg of expected product is obtained.

Rf=0.26 cyclohexane/ethyl acetate 7/3

NMR

4.49 d CH ₂OH 5.40 t CH₂OH 7.65 and 7.88 d H₃, H₅ 6.8 to 6.92 AA′ BB′Ph—OH 9.58 Ph—OH

EXAMPLE 33

2-bromo-4′-hydroxy-6-[3-(dimethylamino)-1-propynyl]-(1,1′-biphenyl)-4-methanol

Stage A: Coupling of the Brominated Diaryl with Propargylamine

Methyl2-bromo-6-(3-dimethylamino-1-propynyl)-4′-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-(1,1′-biphenyl)-4-carboxylate

2 ml of diethylamine, 4 mg of copper iodide, 24 mg of tetrakispalladiumand 0.07 ml of propargylamine are added to a solution under an inertatmosphere of 226.7 mg of the product obtained in Stage A of Example 32in 4 ml of DMF, then the reaction medium is taken to reflux for 30minutes followed by pouring into ice-cooled water, extraction with ethylacetate, drying, evaporation under reduced pressure and purification bychromatography eluting with a cyclohexane/ethyl acetate mixture 60/40.82.3 mg of expected product is obtained.

Rf=0.49 100 % ethyl acetate

NMR CDCl₃ 250 MHz

0.23 s Si(CH ₃)₂ 1.00 s Si—C(CH ₃)₃ 2.08 s N(CH ₃)₂ 3.29 s ≡C—CH ₂—N3.95 s CO₂CH ₃ 6.90 and 7.17 AA′ BB′ Ph—O 8.12 d and 8.24 d H₃, H₅

Stage B: Reduction and Deprotection

2-bromo-4′-hydroxy-6-[3-(dimethylamino)-l-propynyl]-(1,1′-biphenyl)-4-methanol

The operation is carried out in an equivalent manner to Example 32Stages B and C, starting with 367 mg of the product obtained in theprevious stage. 35 mg of expected product A is obtained as well as 44 mgof product B (R₅═CH(OH)nBu, Rf=0.36 dichloromethane/methanol: 9/1).

Product A:

Rf=0.25 dichloromethane/methanol 9/1

NMR DMSO 250 MHz

1.98 s N(CH ₃)₂ 3.29 s ≡C—CH ₂—N 4.50 d CH ₂OH 5.38 t, mobile CH₂OH 6.80and 7.05 AA′ BB′ Ph—O 7.44 d and 7.62 d H₃, H₅ 9.51 mobile H Ph—OH

Product B:2-bromo-alpha-butyl-4′-hydroxy-6-[3-(dimethylamino)-1-propynyl]-(1,1′biphenyl)-methanol

NMR CDCl₃ 250 MHz

0.92 t CH₂—CH₂—CH₂—CH ₃ 1.36 m (4 H) CH₂—CH ₂—CH ₂—CH₃ 1.76 m CH₂—CH₂—CH₂—CH₃ 2.09 s N(CH ₃)₂ 3.30 s ≡C—CH ₂—N 4.63 dd CH(nBu)OH 5.38 t,mobile CH₂OH 6.82 and 7.14 AA′ BB′ Ph—OH 7.44 d and 7.61 d H₃, H₅

EXAMPLE 342-(3-dimethylamino-1-propynyl)-4′-hydroxy-6-nitro-(1,1′-biphenyl)-4-methanol

The operation is carried out in an equivalent manner to Example 33Stages A and B starting with 474.5 mg of the product prepared in Example18 Stage C. 33 mg of the expected product is obtained recrystallizedfrom ethyl ether.

Rf=0.14 CH₂Cl₂/MeOH 90/10

NMR (DMSO, 250 MHz)

1.99 s N(CH ₃)₂ 3.29 s ≡C—CH ₂—N 4.59 d CH ₂OH 5.52 t CH₂OH 6.79 and7.08 d AA′ BB4 Ph—O 7.71 and 7.71 d H₃, H₅ 9.12 ws mobile H Ph—OH

EXAMPLE 35: 4,4″-dihydroxy-(1,1′:2′, 1″-terphenyl)-5′-methanol

Stage A: Demethylation

Methyl 4,4″-dihydroxy-(1.1′:2′,1″-terphenyl)-5′-carboxylate

2.7 g of methyl 4,4″-dimethoxy-(1,1′:2′,1″-terphenyl)-5′-carboxylate(product prepared according to J. Med. Chem. (1989) 32 1814-1820) in 30ml of dichloromethane is cooled down to −30° C., under an inertatmosphere, 2.7 ml of tribromoborane is added and agitation is carriedout at −30° C. for 16 hours. The reaction medium is diluted with asaturated solution of sodium acetate, the aqueous phase is extractedwith ethyl acetate, the organic phase is dried then evaporated. Thecrude reaction product is chromatographed on silica eluting with acyclohexane/ethyl acetate mixture 70/30. In this way 814 mg of expectedproduct is obtained.

Rf=0.31 cyclohexane/ethyl acetate 1/1

Stage B: Acetylation and Reduction

4,4″-dihydroxy-(1,1′:2′,1″-terphenyl)-5′-methanol

260 mg of the product obtained in the previous stage, in 8 ml ofpyridine is cooled down under an inert atmosphere to 0° C., 0.08 ml ofacetic anhydride is added and agitation is carried out for 20 minutes at0° C. then the pyridine is evaporated off under reduced pressure. The340 mg of crude reaction product obtained is used directly in thereduction reaction.

340 mg of the crude product in 6 ml of tetrahydrofuran is cooled downunder an inert atmosphere to 0° C., 96 mg of LiAlH₄ is added andagitation is carried out for 30 minutes at 0° C. The medium is dilutedin an ethyl acetate/water mixture and the aqueous phase is extractedwith ethyl acetate. The organic phase is dried, evaporated under reducedpressure, and the residue is chromatographed on silica eluting with acyclohexane/ethyl acetate mixture 80/20. In this way 66 mg of expectedproduct is obtained.

Rf=0.31 cyclohexane/ethyl acetate 1/1

M.p.=214° C.

I.R. Nujol

absence of C═O

Possible absorption OH/NH

Aromatics 1610, 1590, 1516 cm⁻¹

EXAMPLE 362,6-dichloro-4′-hydroxy-5′-(phenylmethyl)-(1,1′-biphenyl)-4-methanol

Stage A: Deprotection+Rearrangement

2,6-dichloro-4′-hydroxy-5′-(phenylmethyl)-(1,1′-biphenyl)-4-carboxaldehyde

The mixture constituted by 522 mg of the benzylated diphenyl obtained inExample 24 Stage D and 10 ml of trifluoroacetic acid is heated underreflux for 1 hour 30 minutes. The reaction medium is poured into 100 mlof water, then extracted with ethyl acetate, dried and evaporated underreduced pressure. The crude product is purified by reversed-phasechromatography eluting with a methanol/water mixture 60/40 then 80/20.152 mg of expected product is obtained as well as 147 mg of thedebenzylated analogue.

Rf=0.21 cyclohexane/ethyl acetate 80/20

NMR CDCl₃, 200 MHz

4.05 s CH ₂Ph 7.05 m 2 H H₂′, H₆′ 6.95 d 1 H H₃ ′ 7.5 7.2 m 5 H benzyl7.8 s 2 H H₃, H₅ 9.95 s 1 H CHO

Stage B: Reduction

2,6-diphenyl-4′-hydroxy-5′-(phenylmethyl)-(1,1′-biphenyl)-4-methanol

The operation is carried out in an equivalent manner to Example 2starting with 140.4 mg of the aldehyde of the previous stage and 58 mgof expected product is obtained.

Rf=0.27 cyclohexane/ethyl acetate 7/3

NMR CDCl₃, 200 MHz

4.03 s 2 H CH ₂Ph 7.03 m 2 H H₂′, H₆′ 6.86 d 1 H H₃′ 7.16 7.34 m 5 Hbenzyl 7.39 s 2 H H₃, H₅ 4.68 ws 2 H CH ₂OH 1.86 ws 1 H Ph—OH 4.89 ws 1H CH₂OH

By operating in a similar manner to the above examples, starting withthe appropriate compounds, the following compounds were prepared:

EXAMPLE 37

2-bromo 6-[[4-[2-(dimethylamino) ethoxy] phenyl]hydroxymethyl]4′-hydroxy (1,1′-biphenyl) 4-methanol

Rf=0.19 (CH₂Cl₂/MeOH 8/2)

EXAMPLE 38 [6-bromo 4′-hydroxy 4-(hydroxymethyl) (1,1′-biphenyl) 2-yl][4-[2-(dimethylamino) ethoxy] phenyl] methanone.

Rf=0.16 (CH₂Cl₂/MeOH 9/1)

EXAMPLE 39 6′-bromo 4-[2-(dimethylamino) ethoxy] 4″-hydroxy(1,1′:2′,1″-terphenyl) 4′-methanol

Rf=0.13 (CH₂Cl₂/MeOH 9/1)

EXAMPLE 40

4-[2-(dimethylamino) ethoxy] 4″-hydroxy 6′-nitro (1,1′:2′,1″-terphenyl)4′-methanol

Rf=0.11 (CH₂Cl₂/MeOH 9/1)

EXAMPLE 41 6′-chloro 4,4″-dihydroxy (1.1′:2′,1″-terphenyl) 4′-methanol

Rf=0.36 (CH₂Cl₂/MeOH 9/1).

Pharmaceutical Composition

Tablets were prepared corresponding to the following general formula:

product of Example 7  50 mg Excipient (talc, starch, magnesium stearate)120 mg qs for a tablet completed at

Pharmacological Study of the Products of the Invention

Oestrogen Receptor of a Rat's Uterus (ROR):

Female rats of 280-300 g and castrated 24 hours beforehand, aresacrificed, the uteri are removed, then homogenized at 0° C., using ateflon-glass Potter in a buffered solution BS (10 mM Tris, 0.25 Msaccharose, HCl pH 7.4) (1 g of tissue per 10 ml of BS). The homogenateis then ultracentrifuged (209,000 g×30mn.) at 0° C. The supernatantaliquots thus obtained are incubated at 0° C. for 24 hours, with aconstant concentration (2.5 10⁻⁹M) of tritiated oestrodiol in thepresence of increasing concentrations either of unlabelled oestradiol(0-1000×10⁻⁹M), or of unlabelled product to be tested (25000×10⁻⁹M). Theconcentration of bound tritiated oestradiol (B) is then measured in eachincubate by the carbon-dextran adsorption technique.

Human Oestrogen Receptor (HOR)

A cytosolic extract of SF9 cells containing the recombinant humanoestrogen receptor is obtained by overexpression in aninsect-Baculovirus cell system, according to the general methodologydescribed by N. R. WEBB et al. (Journal of Methods in Cell and MolecularBiology, (1990) Vol.2 No. 4, 173-188) and the application of which isdescribed for the expression of human hormonal receptors, for examplethe human glucocorticoid receptor (G. SRINIVASAN et al. MolecularEndocrinology (1990) vol 4 No. 2 209-216).

The BaculoGold Transfection Kit (PharMingen, reference 21000K) is usedto generate the recombinant baculovirus containing the cDNA fragmentdescribed in the expression vector HEGO by L. TORA et al. (The EMBOJournal (1989) vol. 8 No. 7 1981-1986), containing the coding region forthe wild-type human oestrogen receptor with a glycine in position 400.

The recombinant virus thus obtained is used to express the oestrogenreceptor in the SF9 insect cells (ATCC CRL1711), according to the knownmethodology mentioned previously.

2*10⁷ SF9 cells are cultured in a 175 cm² “Falcon” flask in the TNM-FH“SIGMA” medium supplemented by 10% of foetal calf serum (FCS) and by 50microgram/ml of gentamycin. After infection then incubation at 27° C.for 40 to 42 hours, the cells are lysed in 1 ml of lysis buffer (Tris 20mM-HCl pH8, EDTA 0.5 mM, DTT 2 mM, Glycerol 20%, KCl 400 mM) with afreezing-thawing cycle which is repeated another two times. Thesupernatant, containing the recombinant human oestrogen receptor is keptin liquid nitrogen by 0.5 ml doses.

The supernatant is incubated at 0° C. for 24 hours (long t) or 3 hours(short t) with a constant concentration (T) of tritiated oestradiol inthe presence of increasing concentrations of either unlabelledoestradiol (0-1000×10⁻⁹M), or of unlabelled product to be tested(0-25000×10⁻⁹M). The concentration of bound tritiated oestradiol (B) isthen measured in each incubate by the technique of adsorption withcarbon dextran.

Calculation of the Relative Bond Affinity (RBA):

The following two curves are drawn: the percentage of bound tritiatedhormone 100×B/B0 as a function of the logarithm of the concentration ofunlabelled reference hormone or as a function of the concentration ofunlabelled test product.

The straight line of the equation

 I ₅₀ =B0/B0+Bmin/B0)/2=100 (1+Bmin/B0)=50 (1+Bmin/B0)

is determined.

B0=concentration of bound tritiated hormone in the absence of anyunlabelled product.

B=concentration of bound tritiated hormone in the presence of aconcentration X of unlabelled product.

B min=concentration of bound tritiated hormone for an incubation of thistritiated hormone at a concentration (T) in the presence of a largeexcess of unlabelled reference hormone (1000×10⁻⁹M) for the humanreceptor.

The intersections of the straight line I₅₀ and the curves allow theevaluation of the concentrations of unlabelled reference hormone (CH)and of the unlabelled test product (CX) which inhibit by 50% the bindingof the tritiated hormone on the receptor.

The relative bond affinity (RBA) of the test product is calculated bythe equation: RBA=100(CH)/(CX).

The results obtained are as follows:

HOR oestradiol = 100 Examples ROR short t long t (Ex 2) 12.5 425 74 (Ex24) 3 104 35 (Ex 30) 2 24 5 (Ex 26) — — 5.5 (Ex 1) — — 5.5 (Ex 6) — —4.5 (Ex 25) — 12 5 (Ex 13) 0.8 24 7.5 (Ex 28) 2 33 8 (Ex 29) 0.15 — 0.6(Ex 4) 4 — 22 (Ex 18) 5 — 34 (Ex 36) 8 — 0.07 (Ex 7) 9.5 — 50

Conclusion

Certain of the products have an affinity which can range up to 425% ofthe oestradiol which is a new fact for this family of molecules.

What is claimed is:
 1. A method of treating osteoporosis in warm-bloodedanimals comprising administering to warm-blooded animals in need thereofan effective amount to treat osteoporosis of a compound selected fromthe group consisting of a compound of the formula:

wherein R₁ and R₂ are individually selected from the group consisting ofa) hydrogen, halogen, —OH, —CF₃, NO₂, —NH₂, alkoxy of 1 to 8 carbonatoms, alkylthio of 1 to 8 carbon atoms,

wherein R_(A) and R_(B) are individually alkyl of 1 to 8 carbon atoms ortogether with the nitrogen to which they are attached form a saturatedor unsaturated heterocycle of 5 to 6 ring members optionally containinga heteroatom selected from the group consisting of oxygen, sulfur andnitrogen, b) optionally substituted alkyl, alkenyl and alkynyl of up to8 carbon atoms, c) optionally substituted aryl of 6 to 14 carbon atoms,optionally substituted aralkyl of 7 to 15 carbon atoms, —CH(OH)—Y and

Y is selected from the group consisting of i) optionally substitutedalkyl, alkenyl and alkynyl of up to 8 carbon atoms and ii) optionallysubstituted aryl of 6 to 14 carbon atoms or R₁ and R₃ form—CH═CH—CH═CH—, R₃ and R₄ are individually selected from the groupconsisting of hydrogen, halogen and alkyl of 1 to 8 carbon atoms, R₆ andR₇ are individually hydrogen or halogen, R₈ is hydrogen or optionallysubstituted benzyl and R₅ is selected from the group consisting of—[A]—CHO, —[A]—CH₃, —[A]—C(OH)ZZ′ and

—[A]—is selected from the group consisting of a single bond andalkylene, alkenylene and alkynylene of up to 8 carbon atoms and Z, Z′and Z″ are individually selected from the group consisting of a)hydrogen and alkyl, alkenyl and alkynyl of up to 8 carbon atoms and b)optionally substituted aryl of 6 to 14 carbon atoms and its non-toxic,pharmaceutically acceptable addition salts with acids and bases with theproviso that compounds wherein R₅ is

and A is a single bond, Z″ is alkyl of 1 to 8 carbon atoms and R₁ to R₈are all hydrogen are excluded.
 2. The method of claim 1 wherein thecompound is selected from the group consisting of:2,6-dibromo-4′-hydroxy-(1,1′-biphenyl)-4-methanol,2,6-dichloro-4′-hydroxy-(1,1′-biphenyl)-4-methanol,2,6-dinitro-4′-hydroxy-(1,1′-biphenyl)-4-methanol,4,4″-dihydroxy-(1,1′:2′,1″-terphenyl)-5′-methanol,1-[2-chloro-4′-hydroxy-3-methyl-6-isopropyl-(1,1′-biphenyl-4-yl)]-ethanone,2-bromo-4′-hydroxy-6-nitro-(1,1′-biphenyl)-4-methanol,1-[2-chloro-4′-hydroxy3-methyl-6-isopropyl-(1,1′-biphenyl-4-yl)]-ethanol,4′-hydroxy-2-trifluoromethyl-(1,1′-biphenyl)-4-methanol,4′-methyl-2′-trifluoromethyl-(1,1′-biphenyl)-ol,2,6-dichloro-4′-hydroxy-(1,1′-biphenyl)-4-carboxaldehyde,2-chloro-4′-hydroxy-6-isopropyl-(1,1′-biphenyl)-4-methanol,2-chloro-4′-hydroxy-6-trifluoromethyl-(1,1′-biphenyl)-4-methanol,2,6-dichloro-4′-hydroxy-5′-benzyl-(1,1′-biphenyl)-4-methanol, 2-bromo6-[[4-[2-dimethylamino) ethoxy] phenyl] hydroxyethyl] 4′-hydroxy(1,1′-biphenyl) 4-methanol, [6-bromo 4′-hydroxy 4-(hydroxymethyl)(1,1′-biphenyl) 2-yl) [4-[2-dimethylamino) ethoxy] phenyl] methanone,6′-bromo 4-(2-(dimethylamino) ethoxy] 4″-hydroxy (1,1′:2′,1″-terphenyl)4′-methanol, 4-[2-(dimethylamino) ethoxy] 4″-hydroxy 6′-nitro(1,1′:2′,1″-terphenyl) 4′-methanol and 6′-chloro 4,4″-dihydroxy(1,1′:2′,1″-terphenyl) 4′-methanol.
 3. The method of claim 1 wherein theactive compound has the formula:

in which either R′₅ is —[A]—CHO as defined in claim 17 and R₁, R₂, R₃,R₄, R₆, R₇ and R₈ are as defined as in claim 17, it being understoodthat when [A] is a single bond and R₃, R₄, R₆, R₇ and R₈ are hydrogens,R₁ and R₂ cannot simultaneously represent hydrogen, or R′₅ is —C(OH)ZZ′as defined in claim 17 and R₁, R₂, R₃, R₄, R₆, R₇, and R₈ are as definedin claim 17, it being understood that when R₃, R₄, R₆, R₇, and R₈ arehydrogens, R₁ and R₂ cannot simultaneously be hydrogen, or R′₅ is—[A]—CH₃ as defined in claim 17 and R₁, R₂, R₃, R₄, R₆, R₇, and R₈, areas defined in claim 17, it being understood that when R₃, R₄, R₆, R₇ andR₈ are hydrogens, R₁, and R₂ cannot simultaneously each be hydrogen, andit being understood that R₁, R₂, R₃ or R₄ cannot be alkyl or halogen, orR′₅ is [A]—C(O)Z″ as defined in claim 17, R₁, R₂, R₃, R₄, R₆, R₇ and R₈are as defined in claim 17, it being understood that when [A] is asingle bond, R₃, R₄, R₆, R₇ and R₈ are hydrogen, and Z″ is alkyl of 1 to8 carbon atoms, so R₁ and R₂ cannot simultaneously each be hydrogen, orcannot be a nitro or hydroxyl, as well as the addition salts withpharmaceutically acceptable acids and bases.
 4. The method of clam 1wherein the active compound has the formula:

in which R′₁ is an aryl of 6 to 14 carbon atoms and optionallysubstituted, R′₂ is halogen, nitro or amino, as well as the additionsalts with pharmaceutically acceptable acids and bases.
 5. The method ofclaim 1 wherein —[A]— is a single bond.
 6. The method of claim 1 whereinR′₅ is —CH₂OH.
 7. The method of claim 1 wherein R₆, R₇ and R₈ arehydrogen.
 8. The method of claim 1 wherein R₁ and R₂ are individuallyhalogen and R₃, R₄, R₅, R₆, and R₇ and R₈ are hydrogen.
 9. The method ofclaim 4 wherein R′₁ is phenyl substituted with dialkylaminoalkoxy of 3to 16 carbon atoms.